HPTP-β inhibitors

ABSTRACT

Disclosed herein are compounds effective for activation of Tie-2 and inhibition of HPTP-beta. The compounds can provide effective therapy for conditions associated with angiogenesis, for example, ocular conditions. Formulations for increased solubility are disclosed.

CROSS REFERENCE

This Application claims the benefit of U.S. Provisional Application No.61/953,680, filed Mar. 14, 2014, the contents of which is incorporatedherein by reference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Mar. 12, 2015, isnamed Aerpio45725-713.201_SL.txt and is 4,510 bytes in size.

INCORPORATION BY REFERENCE

Each patent, publication, and non-patent literature cited in theapplication is hereby incorporated by reference in its entirety as ifeach was incorporated by reference individually.

BACKGROUND

The eye comprises several structurally and functionally distinctvascular beds, which supply ocular components critical to themaintenance of vision. These include the retinal and choroidalvasculatures, which supply the inner and outer portions of the retina,respectively, and the limbal vasculature located at the periphery of thecornea. Injuries and diseases that impair the normal structure orfunction of these vascular beds are among the leading causes of visualimpairment and blindness. For example, diabetic retinopathy is a commondisease affecting the retinal vasculature, and is a leading cause ofvision loss among the working age population in the United States.Vascularization of the cornea secondary to injury or disease is yetanother category of ocular vascular disease that can lead to severeimpairment of vision.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 displays the NMR data for the final product of step 1 of thesynthesis of compound A.

FIG. 2 displays the HPLC data for the final product of step 1 of thesynthesis of compound A.

FIG. 3 displays the LCMS data for the final product of step 1 of thesynthesis of compound A.

FIG. 4 displays the NMR data for the final product of step 3 of thesynthesis of compound A.

FIG. 5 displays the HPLC data for the final product of step 3 of thesynthesis of compound A.

FIG. 6 displays the LCMS data for the final product of step 3 of thesynthesis of compound A.

FIG. 7 displays the HPLC data for the final product of step 4 of thesynthesis of compound A.

FIG. 8 displays the LCMS data for the final product of step 4 of thesynthesis of compound A.

FIG. 9 displays the NMR data for the final product of step 4 of thesynthesis of compound A.

FIG. 10 displays the HPLC data for the final product of step 5 of thesynthesis of compound A.

FIG. 11 displays the LCMS data for the final product of step 5 of thesynthesis of compound A

FIG. 12 displays the NMR data for the final product of step 5 of thesynthesis of compound A.

FIG. 13 displays the HPLC data for compound A.

FIG. 14 displays the LCMS data for compound A.

FIG. 15 displays the NMR data for compound A.

FIG. 16 displays the NMR data for the starting material for thesynthesis of compound C.

FIG. 17 displays the HPLC data for the starting material for thesynthesis of compound C.

FIG. 18 displays the HPLC data for the final product of step 1 of thesynthesis of compound C.

FIG. 19 displays the NMR data for the final product of step 1 of thesynthesis of compound C.

FIG. 20 displays the HPLC data for the final product of step 3 of thesynthesis of compound C.

FIG. 21 displays the LCMS data for the final product of step 3 of thesynthesis of compound C.

FIG. 22 displays the NMR data for the final product of step 3 of thesynthesis of compound C.

FIG. 23 displays the HPLC data for the final product of step 4 of thesynthesis of compound C.

FIG. 24 displays the LCMS data for the final product of step 4 of thesynthesis of compound C.

FIG. 25 displays the NMR data for the final product of step 4 of thesynthesis of compound C.

FIG. 26 displays the HPLC data for the final product of step 5 of thesynthesis of compound C.

FIG. 27 displays the LCMS data for the final product of step 5 of thesynthesis of compound C.

FIG. 28 displays the NMR data for the final product of step 5 of thesynthesis of compound C.

FIG. 29 displays the HPLC data for compound C.

FIG. 30 displays the LCMS data for compound C.

FIG. 31 displays the NMR data for compound C.

FIG. 32 displays the HPLC data for the final product of step 3 of thesynthesis of compound B.

FIG. 33 displays the LCMS data for the final product of step 3 of thesynthesis of compound B.

FIG. 34 displays the NMR data for the final product of step 3 of thesynthesis of compound B.

FIG. 35 displays the HPLC data for the final product of step 4 of thesynthesis of compound B.

FIG. 36 displays the LCMS data for the final product of step 4 of thesynthesis of compound B.

FIG. 37 displays the NMR data for the final product of step 4 of thesynthesis of compound B.

FIG. 38 displays the HPLC data for the final product of step 5 of thesynthesis of compound B.

FIG. 39 displays the LCMS data for the final product of step 5 of thesynthesis of compound B.

FIG. 40 displays the NMR data for the final product of step 5 of thesynthesis of compound B.

FIG. 41 displays the HPLC data for compound B.

FIG. 42 displays the LCMS data for compound B.

FIG. 43 displays the NMR data for compound B.

FIG. 44 is a western blot representing Tie2 phosphorylation.

FIG. 45 represents ELISA data for Akt phosphorylation.

FIG. 46 depicts the results of two Phase III studies to determine theeffect of intravitreal injections of ranibizumab in patients withdiabetic macular edema.

FIG. 47 depicts the results of a study wherein 4 patients received 5 mgof Compound A subcutaneously twice daily for 28 days and subsequentlywere treated in one or both eyes (7 eyes total) with either ranibizumab(0.3 or 0.5 mg) or aflibercept (2 mg) by intravitreal injection at thediscretion of the study investigator.

FIG. 48 depicts the results of Phase III studies to determine the effectof intravitreal injections of ranibizumab in patients with diabeticmacular edema.

FIG. 49 depicts the increased visual acuity of a study wherein 4patients received 5 mg of a compound disclosed herein subcutaneouslytwice daily for 28 days and subsequently were treated with eitherranibizumab (0.3 or 0.5 mg) or aflibercept (2 mg) by intravitrealinjection.

FIG. 50 graphs changes in central foveal thickness over time in an eyetreated with a drug/antibody combination.

FIG. 51 graphs changes in central foveal thickness over time in an eyetreated with a drug/antibody combination.

FIG. 52 is a graphic representation of in vivo experiments performed in6 week old C57BL/6 mice.

FIG. 53A illustrates the extent of choroidal neovascularization evidentin a control sample stained with FITC-labeled Griffonia simplicifolia(GSA) of the experiment of FIG. 52.

FIG. 53B represents the extent of neovascularization in the choroidaltissue of animals treated with aflibercept, stained with FITC-labeledGriffonia simplicifolia (GSA).

FIG. 53C represents the extent of neovascularization in tissue treatedwith a Tie-2 signaling enhancer, which was stained with FITC-labeledGriffonia simplicifolia (GSA).

FIG. 53D represents the extent of neovascularization present in tissuereceiving a combined therapy of aflibercept and a compound disclosedherein, stained with FITC-labeled Griffonia simplicifolia (GSA).

SUMMARY OF THE INVENTION

In some embodiments, the invention provides a compound of formula:

wherein: Aryl¹ is an aryl group which is substituted or unsubstituted;Aryl² is an aryl group which is substituted or unsubstituted; X isalkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, anamide linkage, an ester linkage, a thioether linkage, a carbamatelinkage, a carbonate linkage, a ureido linkage, a sulfone linkage, anyof which is substituted or unsubstituted, or a chemical bond; and Y isH, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g),any of which is substituted or unsubstituted, or

wherein: L is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L is bound forms an amide linkage, a carbamate linkage, a ureidolinkage, or a sulfonamide linkage, or a chemical bond, or together withany of R^(a), R^(b), R^(c), and R^(d) forms a ring that is substitutedor unsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L, R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a pharmaceutically-acceptable salt, tautomer, orzwitterion thereof.

In some embodiments, the invention provides a compound of formula:

wherein:Aryl¹ is an aryl group which is substituted or unsubstituted; Aryl² isan aryl group which is substituted or unsubstituted; X is alkylene,alkenylene, alkynylene, an ether linkage, an amine linkage, an amidelinkage, an ester linkage, a thioether linkage, a carbamate linkage, acarbonate linkage, a ureido linkage, a sulfone linkage, any of which issubstituted or unsubstituted, or a chemical bond; L is alkylene,alkenylene, or alkynylene, any of which is substituted or unsubstituted,or together with the nitrogen atom to which L is bound forms an amidelinkage, a carbamate linkage, a ureido linkage, or a sulfonamidelinkage, or a chemical bond, or together with any of R^(a), R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(b), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(b) is H,alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a pharmaceutically-acceptable salt, tautomer, orzwitterion thereof.

In some embodiments, the invention provides a pharmaceutical compositioncomprising two Tie-2 activators, wherein the two Tie-2 activators arestereoisomers of one another, wherein the pharmaceutical composition isin a unit dosage form.

In some embodiments, the invention provides a pharmaceutical compositioncomprising a Tie-2 activator and a stereoisomer of the Tie-2 activator,wherein the stereoisomer activates Tie-2 with a potency that is fromabout 0.001% to about 100% the potency of the Tie-2 activator.

In some embodiments, the invention provides a method comprisingcontacting with a reaction mixture a compound of formula:

wherein:Aryl¹ is an aryl group which is substituted or unsubstituted; Aryl² isan aryl group which is substituted or unsubstituted; X is alkylene,alkenylene, alkynylene, an ether linkage, an amine linkage, an amidelinkage, an ester linkage, a thioether linkage, a carbamate linkage, acarbonate linkage, a ureido linkage, a sulfone linkage, any of which issubstituted or unsubstituted, or a chemical bond; L is alkylene,alkenylene, or alkynylene, any of which is substituted or unsubstituted,or together with the nitrogen atom to which L is bound forms an amidelinkage, a carbamate linkage, a ureido linkage, or a sulfonamidelinkage, or a chemical bond, or together with any of R^(a), R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(b), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(b) is H,alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a salt, tautomer, or zwitterion thereof, wherein astereocenter of the compound or salt thereof inverts, thereby providinga stereoisomer of the compound or a salt, tautomer, or zwitterion of thestereoisomer.

DETAILED DESCRIPTION

Provided herein are compounds and methods of treating ocular disordersthat are characterized by vascular instability, vascular leakage, andneovascularization. HPTP-β is a member of the receptor-like family ofthe protein tyrosine phosphatases (PTPases). HPTP-β is a transmembraneprotein found primarily in endothelial cells that displays structuraland functional similarity to cell adhesion molecules (CAMs). HPTP-β isunique among receptor-like PTPases in that it contains a singlecatalytic domain. One of the main functions of HPTP-β is to regulateTie-2 negatively.

Tie-2 is a receptor tyrosine kinase found almost exclusively inendothelial cells. The principle regulators of Tie-2 phosphorylation areAngiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2). Upon Ang-1 binding toTie-2, the level of Tie-2 receptor phosphorylation increases. Theduration of Tie-2 receptor phosphorylation is regulated by HPTP-β, whichcleaves off the phosphate. Tie-2 receptor phosphorylation helps maintainendothelial cell proximity; therefore, the duration of Tie-2 receptorphosphorylation is an important determinant of endothelial cellproximity. For example, when severe inflammation occurs, the capillaryendothelial cells separate, allowing proteins to enter the interstitialspace. Separation of the capillary endothelial cells, and subsequentleak of proteins in the interstitial space, is known as vascular leak,and can lead to dangerous hypotension, edema, hemoconcentration, andhypoalbuminemia.

The present disclosure relates to compositions and methods for treatingconditions, such as ocular diseases, wherein neovasculatization andvascular leakage can be present. These diseases can display an elevatedangiogenic response in ocular vessels. The present disclosure describesHPTP-β inhibitors that can provide vascular stabilization.

Human Protein Tyrosine Phosphatase-beta (HPTP-β) Inhibitors.

Compounds disclosed herein can be effective as Tie-2 activators. Thecompounds can effect that activity, for example, by binding to orinhibiting HPTP-β. Such compounds can bind to HPTP-β, for example, bymimicking the binding mechanism of a native substrate, such as aphosphorylated compound. A compound can be a phosphate mimetic orbioisostere, for example, a sulfamic acid. The compound could also bederived from an amino acid building block or comprise an amino acidbackbone for efficiency and economy of synthesis.

In some embodiments, a compound of the invention is a compound of theformula:

wherein:Aryl¹ is an aryl group which is substituted or unsubstituted; Aryl² isan aryl group which is substituted or unsubstituted; X is alkylene,alkenylene, alkynylene, an ether linkage, an amine linkage, an amidelinkage, an ester linkage, a thioether linkage, a carbamate linkage, acarbonate linkage, a ureido linkage, a sulfone linkage, any of which issubstituted or unsubstituted, or a chemical bond; and Y is H, aryl,heteroaryl, NH(aryl), NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g), any ofwhich is substituted or unsubstituted, or

wherein:L is alkylene, alkenylene, or alkynylene, any of which is substituted orunsubstituted, or together with the nitrogen atom to which L is boundforms an amide linkage, a carbamate linkage, a ureido linkage, or asulfonamide linkage, or a chemical bond, or together with any of R^(a),R^(b), R^(c), and R^(d) forms a ring that is substituted orunsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L, R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a pharmaceutically-acceptable salt, tautomer, orzwitterion thereof.

In some embodiments, aryl¹ is substituted or unsubstituted phenyl, aryl²is substituted or unsubstituted heteroaryl, and X is alkylene. In someembodiments, aryl¹ is substituted phenyl, aryl² is substitutedheteroaryl, and X is methylene.

In some embodiments, a compound is of the formula:

wherein aryl¹ is para-substituted phenyl, aryl² is substitutedheteroaryl; X is methylene; L is alkylene, alkenylene, or alkynylene,any of which is substituted or unsubstituted, or together with thenitrogen atom to which L is bound forms an amide linkage, a carbamatelinkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond;R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(b) is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, any of which is substituted or unsubstituted; R^(c) isH or alkyl which is substituted or unsubstituted; and R^(d) is H oralkyl which is substituted or unsubstituted.

In some embodiments, aryl¹ is para-substituted phenyl; aryl² is asubstituted thiazole moiety; X is methylene; L together with thenitrogen atom to which L is bound forms a carbamate linkage; R^(a) isalkyl, which is substituted or unsubstituted; R^(b) is arylalkyl, whichis substituted or unsubstituted; R^(c) is H; and R^(d) is H.

In some embodiments, Aryl² is:

wherein R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, a carboxylic acid group, a carboxaldehydegroup, an ester group, an amine group, an amide group, a carbonategroup, a carbamate group, a ureido group, a thioether group, a thioestergroup, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; and R^(f) is H, OH, F, Cl, Br, I, CN,alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylicacid group, a carboxaldehyde group, an ester group, an amine group, anamide group, a carbonate group, a carbamate group, a ureido group, athioether group, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted.

In some embodiments, R^(e) is H, OH, F, Cl, Br, I, alkyl, an alkoxygroup, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, any of which is substituted or unsubstituted; and R^(f)is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted. In some embodiments, R^(e) is H,OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substitutedor unsubstituted and R^(f) is alkyl, aryl, heterocyclyl, or heteroaryl,any of which is substituted or unsubstituted. In some embodiments, aryl¹is 4-phenylsulfamic acid; R^(a) is alkyl, which is substituted orunsubstituted; R^(b) is arylalkyl, which is substituted orunsubstituted; R^(e) is H; and R^(f) is heteroaryl. In some embodiments,aryl¹ is 4-phenylsulfamic acid; R^(a) is alkyl; which is substituted orunsubstituted; R^(b) is arylalkyl, which is substituted orunsubstituted; R^(e) is H; and R^(f) is alkyl.

In some embodiments, Aryl² is:

wherein R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, a carboxylic acid group, a carboxaldehydegroup, an ester group, an amine group, an amide group, a carbonategroup, a carbamate group, a ureido group, a thioether group, a thioestergroup, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, R^(f) is H, OH, F, Cl, Br, I, CN, alkyl,alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acidgroup, a carboxaldehyde group, an ester group, an amine group, an amidegroup, a carbonate group, a carbamate group, a ureido group, a thioethergroup, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted. In some embodiments, R^(e) is H,OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; and R^(f) is H, OH, F, Cl, Br, I, alkyl,an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted. In some embodiments, R^(e) is H, OH, F, Cl, Br, I, alkyl,or an alkoxy group, any of which is substituted or unsubstituted; andR^(f) is alkyl, aryl, heterocyclyl, or heteroaryl, any of which issubstituted or unsubstituted. In some embodiments, aryl¹ is4-phenylsulfamic acid; R^(a) is alkyl, which is substituted orunsubstituted; R^(b) is arylalkyl, which is substituted orunsubstituted; R^(e) is H; and R^(f) is heteroaryl.

In some embodiments, a substituted phenyl group is:

wherein:each of R^(ph1), R^(ph2), R^(ph3), R^(ph4), and R^(ph5) is independentlyH, OH, F, Cl, Br, I, CN, sulfamic acid, tosylate, mesylate, triflate,besylate, alkyl, alkenyl, alkynyl, an alkoxy group, a sulfhydryl group,a nitro group, a nitroso group, an azido group, a sulfoxide group, asulfone group, a sulfonamide group, an ether group, a carboxylic acidgroup, a carboxaldehyde group, an ester group, an amine group, an amidegroup, a carbonate group, a carbamate group, a ureido group, a thioethergroup, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Illustrative compounds include the following:

Optional Substituents for Chemical Groups.

Non-limiting examples of optional substituents include hydroxyl groups,sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups,cyano groups, azido groups, sulfoxide groups, sulfone groups,sulfonamide groups, carboxyl groups, carboxaldehyde groups, iminegroups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenylgroups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups,aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups,acyl groups, acyloxy groups, carbamate groups, amide groups, ureidogroups, and ester groups.

Non-limiting examples of alkyl and alkylene groups include straight,branched, and cyclic alkyl and alkylene groups. An alkyl group can be,for example, a C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃,C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, C₂₂, C₂₃, C₂₄, C₂₅, C₂₆, C₂₇,C₂₈, C₂₉, C₃₀, C₃₁, C₃₂, C₃₃, C₃₄, C₃₅, C₃₆, C₃₇, C₃₈, C₃₉, C₄₀, C₄₁,C₄₂, C₄₃, C₄₄, C₄₅, C₄₆, C₄₇, C₄₈, C₄₉, or C₅₀ group that is substitutedor unsubstituted.

Non-limiting examples of straight alkyl groups include methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

Branched alkyl groups include any straight alkyl group substituted withany number of alkyl groups. Non-limiting examples of branched alkylgroups include isopropyl, isobutyl, sec-butyl, and t-butyl.

Non-limiting examples of cyclic alkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctylgroups. Cyclic alkyl groups also include fused-, bridged-, andspiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclicalkyl group can be substituted with any number of straight, branched, orcyclic alkyl groups.

Non-limiting examples of alkenyl and alkenylene groups include straight,branched, and cyclic alkenyl groups. The olefin or olefins of an alkenylgroup can be, for example, E, Z, cis, trans, terminal, or exo-methylene.An alkenyl or alkenylene group can be, for example, a C₂, C₃, C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀,C₂₁, C₂₂, C₂₃, C₂₄, C₂₅, C₂₆, C₂₇, C₂₈, C₂₉, C₃₀, C₃₁, C₃₂, C₃₃, C₃₄,C₃₅, C₃₆, C₃₇, C₃₈, C₃₉, C₄₀, C₄₁, C₄₂, C₄₃, C₄₄, C₄₅, C₄₆, C₄₇, C₄₈,C₄₉, or C₅₀ group that is substituted or unsubstituted.

Non-limiting examples of alkynyl or alkynylene groups include straight,branched, and cyclic alkynyl groups. The triple bond of an alkylnyl oralkynylene group can be internal or terminal. An alkylnyl or alkynylenegroup can be, for example, a C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, C₂₂, C₂₃, C₂₄, C₂₅,C₂₆, C₂₇, C₂₈, C₂₉, C₃₀, C₃₁, C₃₂, C₃₃, C₃₄, C₃₅, C₃₆, C₃₇, C₃₈, C₃₉,C₄₀, C₄₁, C₄₂, C₄₃, C₄₄, C₄₅, C₄₆, C₄₇, C₄₈, C₄₉, or C₅₀ group that issubstituted or unsubstituted.

A halo-alkyl group can be any alkyl group substituted with any number ofhalogen atoms, for example, fluorine, chlorine, bromine, and iodineatoms. A halo-alkenyl group can be any alkenyl group substituted withany number of halogen atoms. A halo-alkynyl group can be any alkynylgroup substituted with any number of halogen atoms.

An alkoxy group can be, for example, an oxygen atom substituted with anyalkyl, alkenyl, or alkynyl group. An ether or an ether group comprisesan alkoxy group. Non-limiting examples of alkoxy groups include methoxy,ethoxy, propoxy, isopropoxy, and isobutoxy.

An aryl group can be heterocyclic or non-heterocyclic. An aryl group canbe monocyclic or polycyclic. An aryl group can be substituted with anynumber of substituents described herein, for example, hydrocarbylgroups, alkyl groups, alkoxy groups, and halogen atoms. Non-limitingexamples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl,pyridyl, imidazolyl, thiophenyl, and furyl.

An aryloxy group can be, for example, an oxygen atom substituted withany aryl group, such as phenoxy.

An aralkyl group can be, for example, any alkyl group substituted withany aryl group, such as benzyl.

An arylalkoxy group can be, for example, an oxygen atom substituted withany aralkyl group, such as benzyloxy.

A heterocycle can be any ring containing a ring atom that is not carbon,for example, N, O, S, P, Si, B, or any other heteroatom. A heterocyclecan be substituted with any number of substituents, for example, alkylgroups and halogen atoms. A heterocycle can be aromatic (heteroaryl) ornon-aromatic. Non-limiting examples of heterocycles include pyrrole,pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine,imidazole, thiophene, furan, tetrahydrofuran, pyran, andtetrahydropyran.

An acyl group can be, for example, a carbonyl group substituted withhydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl,arylalkoxy, or a heterocycle. Non-limiting examples of acyl includeacetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl,and ethoxycarbonyl.

An acyloxy group can be an oxygen atom substituted with an acyl group.An ester or an ester group comprises an acyloxy group. A non-limitingexample of an acyloxy group, or an ester group, is acetate.

A carbamate group can be an oxygen atom substituted with a carbamoylgroup, wherein the nitrogen atom of the carbamoyl group isunsubstituted, monosubstituted, or disubstituted with one or more ofhydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogenatom is disubstituted, the two substituents together with the nitrogenatom can form a heterocycle.

A compound described herein can be at least 1% pure, at least 2% pure,at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure,at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure,at least 11% pure, at least 12% pure, at least 13% pure, at least 14%pure, at least 15% pure, at least 16% pure, at least 17% pure, at least18% pure, at least 19% pure, at least 20% pure, at least 21% pure, atleast 22% pure, at least 23% pure, at least 24% pure, at least 25% pure,at least 26% pure, at least 27% pure, at least 28% pure, at least 29%pure, at least 30% pure, at least 31% pure, at least 32% pure, at least33% pure, at least 34% pure, at least 35% pure, at least 36% pure, atleast 37% pure, at least 38% pure, at least 39% pure, at least 40% pure,at least 41% pure, at least 42% pure, at least 43% pure, at least 44%pure, at least 45% pure, at least 46% pure, at least 47% pure, at least48% pure, at least 49% pure, at least 50% pure, at least 51% pure, atleast 52% pure, at least 53% pure, at least 54% pure, at least 55% pure,at least 56% pure, at least 57% pure, at least 58% pure, at least 59%pure, at least 60% pure, at least 61% pure, at least 62% pure, at least63% pure, at least 64% pure, at least 65% pure, at least 66% pure, atleast 67% pure, at least 68% pure, at least 69% pure, at least 70% pure,at least 71% pure, at least 72% pure, at least 73% pure, at least 74%pure, at least 75% pure, at least 76% pure, at least 77% pure, at least78% pure, at least 79% pure, at least 80% pure, at least 81% pure, atleast 82% pure, at least 83% pure, at least 84% pure, at least 85% pure,at least 86% pure, at least 87% pure, at least 88% pure, at least 89%pure, at least 90% pure, at least 91% pure, at least 92% pure, at least93% pure, at least 94% pure, at least 95% pure, at least 96% pure, atleast 97% pure, at least 98% pure, at least 99% pure, at least 99.1%pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, atleast 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least99.8% pure, or at least 99.9% pure on a chemical, optical, isomeric,enantiomeric, or diastereomeric basis. Purity can be assessed, forexample, by HPLC, MS, LC/MS, melting point, or NMR.

Pharmaceutically-Acceptable Salts.

The invention provides the use of pharmaceutically-acceptable salts ofany compound described herein. Pharmaceutically-acceptable saltsinclude, for example, acid-addition salts and base-addition salts. Theacid that is added to the compound to form an acid-addition salt can bean organic acid or an inorganic acid. A base that is added to thecompound to form a base-addition salt can be an organic base or aninorganic base. In some embodiments, a pharmaceutically-acceptable saltis a metal salt. In some embodiments, a pharmaceutically-acceptable saltis an ammonium salt.

Metal salts can arise from the addition of an inorganic base to acompound of the invention. The inorganic base consists of a metal cationpaired with a basic counterion, such as, for example, hydroxide,carbonate, bicarbonate, or phosphate. The metal can be an alkali metal,alkaline earth metal, transition metal, or main group metal. In someembodiments, the metal is lithium, sodium, potassium, cesium, cerium,magnesium, manganese, iron, calcium, strontium, cobalt, titanium,aluminum, copper, cadmium, or zinc.

In some embodiments, a metal salt is a lithium salt, a sodium salt, apotassium salt, a cesium salt, a cerium salt, a magnesium salt, amanganese salt, an iron salt, a calcium salt, a strontium salt, a cobaltsalt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt,or a zinc salt.

Ammonium salts can arise from the addition of ammonia or an organicamine to a compound of the invention. In some embodiments, the organicamine is triethyl amine, diisopropyl amine, ethanol amine, diethanolamine, triethanol amine, morpholine, N-methylmorpholine, piperidine,N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine,pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine.

In some embodiments, an ammonium salt is a triethyl amine salt, adiisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, atriethanol amine salt, a morpholine salt, an N-methylmorpholine salt, apiperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt,a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazolesalt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or apipyrazine salt.

Acid addition salts can arise from the addition of an acid to a compoundof the invention. In some embodiments, the acid is organic. In someembodiments, the acid is inorganic. In some embodiments, the acid ishydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid,isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbicacid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid,formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid,propionic acid, butyric acid, fumaric acid, succinic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

In some embodiments, the salt is a hydrochloride salt, a hydrobromidesalt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfatesalt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactatesalt, a salicylate salt, a tartrate salt, an ascorbate salt, agentisinate salt, a gluconate salt, a glucaronate salt, a saccaratesalt, a formate salt, a benzoate salt, a glutamate salt, a pantothenatesalt, an acetate salt, a propionate salt, a butyrate salt, a fumaratesalt, a succinate salt, a methanesulfonate salt, an ethanesulfonatesalt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citratesalt, an oxalate salt, or a maleate salt.

Optical Activity.

Optical activity is the ability of a chiral molecule to rotate a planeof polarized light. Molecules that can rotate a beam of light areoptically active. Those that rotate light clockwise are dextrorotatory,and those that rotate light counterclockwise are levorotatory. If onlyone enantiomer is present in a sample, the sample is optically pure.When both enatiomers are present in equal amounts, the effects ofoptical rotation sum to zero. If a mixture of enantiomers is present,but one enatiomer is in excess, the sample is optically active.

Optical activity can be measured using a polarimeter, which determinesthe specific rotation of a substance based upon the temperature,wavelength of light used, and concentration of the substance, expressedas the angle to which the material causes polarized light to rotate. Apolarimeter holds a sample tube, through which light is passed via apolarizing filter. The analyzing lens is rotated such that the light isvisible to the user; the amount (expressed in degrees) that the lensmust be rotated to make the light visible is known as the observedrotation, and is used to calculate the specific rotation of the samplebeing tested.

The specific rotation of a sample can be about +1°, about −1°, about+2°, about −2°, about +3°, about −3°, about +4°, about −4°, about +5°,about −5°, about +6°, about −6°, about +7°, about −7°, about +8°, about−8°, about +9°, about −9°, about +10°, about −10°, about +11°, about−11°, about +12°, about −12°, about +13°, about −13°, about +14°, about14°, about +15°, about −15°, about +16°, about −16°, about +17°, about−17°, about +18°, about −18°, about +19°, about −19°, about +20°, about−20°, about +21°, about −21°, about +22°, about −22°, about +23°, about−23°, about +24°, about −24°, about +25°, about −25°, about +26°, about−26°, about +27°, about −27°, about +28°, about −28°, about +29°, about−29°, about +30°, about −30°, about +40°, about −40°, about +50°, about−50°, about +60°, about −60°, about +70°, about −70°, about +80°, about−80°, about +90°, about −90°, about +100°, about −100°, about +110°,about −110°, about +120°, about −120°, about +130°, about −130°, about+140°, about −140°, about +150°, about −150°, about +160°, about −160°,about +170°, about −170°, about +180°, about −180°, about +190°, about−190°, about +200°, about −200°, about +210°, about −210°, about +220°,about −220°, about +230°, about −230°, about +240°, about −240°, about+250°, about −250°, about +260°, about −260°, about +270°, about −270°,about +280°, about −280°, about +290°, about −290°, about +300°, about−300°, about +310°, about −310°, about +320°, about −320°, about +330°,about −330°, about +340°, about −340°, about +350°, about −350°, about+360°, or about −360°.

Circular dichroism (CD) is the difference in absorption of left-handedcircularly polarised light (L-CPL) and right-handed circularly polarisedlight (R-CPL), and occurs when a molecule contains one or more chirallight-absorbing groups. Optically active chiral molecules preferentiallyabsorb one direction of the polarized light, causing differentlypolarized light beams to travel through an optically active medium withdifferent velocities.

In some embodiments, the pharmaceutical composition disclosed hereincontains a mixture of stereoisomers. A stereoisomer can be present as apercentage of the total mixture of about 0.0001%, about 0.0005%, about0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.5%,about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about30%, about 35%, about 40%, about 45%, or about 50%.

Optical activity of a sample can change, for example, through theracemization, epimerization, or inversion of stereocenters of compoundsin the same. For example, if a compound of the following formula:

is subjected to suitable reaction conditions or contacted with asuitable reagent or catalyst, then a stereocenter of the compound canchange, for example, to provide a compound of any of the followingformulae, or a mixture thereof:

or a stereoisomer, tautomer, or salt thereof.

A compound having a stereocenter and a starting material having astereocenter can be coupled together under suitable reaction conditionsor in the presence of a suitable reagent or catalyst, and undergoinversion of one or more stereocenters during the reaction. For example,a compound of formula:

can be coupled to a starting material of formula:

wherein N group is a functional group that contains a nitrogen atom, toprovide a product of formula:

or a stereoisomer, tautomer, or salt thereof.

Nonlimiting examples of suitable reagents and catalysts include acids,bases, coupling agents, and additives. Non-limiting examples of acidsinclude hydrochloric acid, hydrobromic acid, hydroiodic acid, nitricacid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid,tartaric acid, acetic acid, succinic acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,citric acid, and triflic acid. Non-limiting examples of bases includelithium hydroxide, sodium hydroxide, potassium hydroxide, lithiumalkoxide, sodium alkoxide, potassium alkoxide, lithium methoxide, sodiummethoxide, potassium methoxide, lithium ethoxide, sodium ethoxide,potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassiumisopropoxide, lithium carbonate, sodium carbonate, potassium carbonate,lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithiumphosphate, sodium phosphate, potassium phosphate, dilithium phosphate,disodium phosphate, dipotassium phosphate, trilithium phosphate,trisodium phosphate, tripotassium phosphate, ammonia, a trialkyl amine,ammonium hydroxide, trimethyl amine, triethyl amine, tribenzyl amine,diisopropylethyl amine, DBU, DBN, pyridine, imidazole, 2,6-lutidine,quinoline, 1,8-bis(dimethylamino)naphthylene, N-methylmorpholine,N-methylpiperidine, and dimethylaminopyridine. Non-limiting examples ofcoupling agents inclide DCC, DIC, EDCI, HBTU, TBTU, HATU, HCTU, BOP,PyBOP, PyAOP, PyBroP, TSTU, TOTU, TPTU, TDBTU, DEPBT, CDI, T3P, andpivaloyl chloride. Non-limiting examples of additives include silica,alumina, magnesium oxide, titanium oxide, zeolite, active carbon,montmorillonite, HOBt, and HOAt.

Antibodies.

Compounds of the invention can be co-formulated or co-administered withantibodies, for example, anti-VEGF agents. Non-limiting examples of suchantibodies include ranibizumab, bevacizumab, and aflibercept.

An antibody can comprise a heavy chain and a light chain. In someembodiments, the heavy chain comprises SEQ ID NO:1:

GluValGlnLeuValGluSerGlyGlyGlyLeuValGlnProGlyGlySerLeuArgLeuSerCysAlaAlaSerGlyTyrAspPheThrHisTyrGlyMetAsnTrpValArgGlnAlaProGlyLysGlyLeuGluTrpValGlyTrpIleAsnThrTyrThrGlyGluProThrTyrAlaAlaAspPheLysArgArgPheThrPheSerLeuAspThrSerLysSerThrAlaTyrLeuGlnMetAsnSerLeuArgAlaGluAspThrAlaValTyrTyrCysAlaLysTyrProTyrTyrTyrGlyThrSerHisTrpTyrPheAspValTrpGlyGlnGlyThrLeuValThrValSerSerAlaSerThrLysGlyProSerValPheProLeuAlaProSerSerLysSerThrSerGlyGlyThrAlaAlaLeuGlyCysLeuValLysAspTyrPheProGluProValThrValSerTrpAsnSerGlyAlaLeuThrSerGlyValHisThrPheProAlaValLeuGlnSerSerGlyLeuTyrSerLeuSerSerValValThrValProSerSerSerLeuGlyThrGlnThrTyrIleCysAsnValAsnHisLysProSerAsnThrLysValAspLysLysValGluProLys SerCysAspLysThrHisLeu.

In some embodiments, the heavy chain is SEQ ID NO:1.

In some embodiments, the light chain comprises SEQ ID NO:2:

AspIleGlnLeuThrGlnSerProSerSerLeuSerAlaSerValGlyAspArgValThrIleThrCysSerAlaSerGlnAspIleSerAsnTyrLeuAsnTrpTyrGlnGlnLysProGlyLysAlaProLysValLeuIleTyrPheThrSerSerLeuHisSerGlyValProSerArgPheSerGlySerGlySerGlyThrAspPheThrLeuThrIleSerSerLeuGlnProGluAspPheAlaThrTyrTyrCysGlnGlnTyrSerThrValProTrpThrPheGlyGlnGlyThrLysValGluIleLysArgThrValAlaAlaProSerValPheIlePheProProSerAspGluGlnLeuLysSerGlyThrAlaSerValValCysLeuLeuAsnAsnPheTyrProArgGluAlaLysValGlnTrpLysValAspAsnAlaLeuGlnSerGlyAsnSerGlnGluSerValThrGluGlnAspSerLysAspSerThrTyrSerLeuSerSerThrLeuThrGlnSerSerGlyLeuTyrSerLeuSerSerValValThrValProSerSerSerLeuGlyThrGlnThrTyrIleCysAsnValAsnHisLysProSerAsnThrLysValAspLysLysValGluProLys SerCysAspLysThrHisLeu.

In some embodiments, the light chain is SEQ ID NO:2.

An antibody used herein can comprise one or both of SEQ ID NOs: 1 and 2.An antibody used herein can consist of one or both of SEQ ID NOs: 1 and2.

Formulations.

The disclosed solubilizing systems can comprise one or morepharmaceutically acceptable agents, which alone or in combinationsolubilize a compound herein or a pharmaceutically acceptable saltthereof.

Alcohols.

A non-limiting example of a solubilizing agent includes an organicsolvent. Non-limiting examples of organic solvents include alcohols, forexample, C₁-C₄ linear alkyl, C₃-C₄ branched alkyl, ethanol, ethyleneglycol, glycerin, 2-hydroxypropanol, propylene glycol, maltitol,sorbitol, xylitol; substituted or unsubstituted aryl, and benzylalcohol.

Cyclodextrins.

Non-limiting examples of cyclodextrins include β-cyclodextrin, methylβ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin sodium salt, and 2-hydroxypropyl-β-cyclodextrin. Acyclodextrin can possess a large cyclic structure with a channel passingthrough the center of the structure. The interior of the cyclodextrincan be hydrophobic, and interact favorably with hydrophobic molecules.The exterior of the cyclodextrin can be highly hydrophilic owing to theseveral hydroxyl groups exposed to bulk solvent. Capture of ahydrophobic molecule, such as a compound disclosed herein, in thechannel of the cyclodextrin can result in the formation of a complexstabilized by non-covalent hydrophobic interactions. The complex can besoluble in water, and carry the captured hydrophobic molecule into thebulk solvent.

The disclosed solubilizing systems comprise2-hydroxypropyl-beta-cyclodextrin (HP-CD).2-Hydroxypropyl-β-cyclodextrin [CAS No. 128446-35-5] is commerciallyavailable as Cavitron™. 2-Hydroxypropyl-β-cyclodextrin, also describedknown as hydroxypropyl-β-cyclodextrin,2-hydroxypropyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin orHPβCD, can be represented by either of the following formulae:

The average molecular weight of Cavitron™, is approximately 1396 Da,wherein the average degree of substitution is from about 0.5 to about1.3 units of 2-hydroxypropyl per ring glucose unit.

In one embodiment, a formulation disclosed herein can comprise a ratioof about 20 parts of a compound herein or a pharmaceutically acceptablesalt thereof to about 1 part solubilizing system (about 20: about 1), toabout 1 part of the compound herein or a pharmaceutically acceptablesalt thereof to about 20 parts solubilizing system (about 1: about 20).For example, a formulation containing about 100 mg of a compound hereinor a pharmaceutically acceptable salt thereof can contain from about 5mg to about 2000 mg of a solubilizing agent, such as a cyclodextrin. Inanother embodiment, the ratio can be based on number, or moles, orcompound compared to number, or moles, of the solubilizing system.

The following are non-limiting examples of ratios of a compound hereinand a solubilizing agent, such as a cyclodextrin. The following examplesalternatively describe the ratio of a solubilizing agent, such as acyclodextrin, and a compound herein. The ratio can be: about 20: about1; about 19.9: about 1; about 19.8: about 1; about 19.7: about 1; about19.6: about 1; about 19.5: about 1; about 19.4: about 1; about 19.3:about 1; about 19.2: about 1; about 19.1: about 1; about 19: about 1;about 18.9: about 1; about 18.8: about 1; about 18.7: about 1; about18.6: about 1; about 18.5: about 1; about 18.4: about 1; about 18.3:about 1; about 18.2: about 1; about 18.1: about 1; about 18: about 1;about 17.9: about 1; about 17.8: about 1; about 17.7: about 1; about17.6: about 1; about 17.5: about 1; about 17.4: about 1; about 17.3:about 1; about 17.2: about 1; about 17.1: about 1; about 17: about 1;about 16.9: about 1; about 16.8: about 1; about 16.7: about 1; about16.6: about 1; about 16.5: about 1; about 16.4: about 1; about 16.3:about 1; about 16.2: about 1; about 16.1: about 1; about 16: about 1;about 15.9: about 1; about 15.8: about 1; about 15.7: about 1; about15.6: about 1; about 15.5: about 1; about 15.4: about 1; about 15.3:about 1; about 15.2: about 1; about 15.1: about 1; about 15: about 1;about 14.9: about 1; about 14.8: about 1; about 14.7: about 1; about14.6: about 1; about 14.5: about 1; about 14.4: about 1; about 14.3:about 1; about 14.2: about 1; about 14.1: about 1; about 14: about 1;about 13.9: about 1; about 13.8: about 1; about 13.7: about 1; about13.6: about 1; about 13.5: about 1; about 13.4: about 1; about 13.3:about 1; about 13.2: about 1; about 13.1: about 1; about 13: about 1;about 12.9: about 1; about 12.8: about 1; about 12.7: about 1; about12.6: about 1; about 12.5: about 1; about 12.4: about 1; about 12.3:about 1; about 12.2: about 1; about 12.1: about 1; about 12: about 1;about 11.9: about 1; about 11.8: about 1; about 11.7: about 1; about11.6: about 1; about 11.5: about 1; about 11.4: about 1; about 11.3:about 1; about 11.2: about 1; about 11.1 about 1; about 11: about 1;about 10.9: about 1; about 10.8: about 1; about 10.7: about 1; about10.6: about 1; about 10.5: about 1; about 10.4: about 1; about 10.3:about 1; about 10.2: about 1; about 10.1: about 1; about 10: about 1;about 9.9: about 1; about 9.8: about 1; about 9.7: about 1; about 9.6:about 1; about 9.5: about 1; about 9.4: about 1; about 9.3: about 1;about 9.2: about 1; about 9.1: about 1; about 9: about 1; about 8.9:about 1; about 8.8: about 1; about 8.7: about 1; about 8.6: about 1;about 8.5: about 1; about 8.4: about 1; about 8.3: about 1; about 8.2:about 1; about 8.1: about 1; about 8: about 1; about 7.9: about 1; about7.8: about 1; about 7.7: about 1; about 7.6: about 1; about 7.5: about1; about 7.4: about 1; about 7.3: about 1; about 7.2: about 1; about7.1: about 1; about 7: about 1; about 6.9: about 1; about 6.8: about 1;about 6.7: about 1; about 6.6: about 1; about 6.5: about 1; about 6.4:about 1; about 6.3: about 1; about 6.2: about 1; about 6.1: about 1;about 6: about 1; about 5.9: about 1; about 5.8: about 1; about 5.7:about 1; about 5.6: about 1; about 5.5: about 1; about 5.4: about 1;about 5.3: about 1; about 5.2: about 1; about 5.1: about 1; about 5:about 1; about 4.9: about 1; about 4.8: about 1; about 4.7: about 1;about 4.6: about 1; about 4.5: about 1; about 4.4: about 1; about 4.3:about 1; about 4.2: about 1; about 4.1: about 1; about 4: about 1; about3.9: about 1; about 3.8: about 1; about 3.7: about 1; about 3.6: about1; about 3.5: about 1; about 3.4: about 1; about 3.3: about 1; about3.2: about 1; about 3.1: about 1; about 3: about 1; about 2.9: about 1;about 2.8: about 1; about 2.7: about 1; about 2.6: about 1; about 2.5:about 1; about 2.4: about 1; about 2.3: about 1; about 2.2: about 1;about 2.1: about 1; about 2: about 1; about 1.9: about 1; about 1.8:about 1; about 1.7: about 1; about 1.6: about 1; about 1.5: about 1;about 1.4: about 1; about 1.3: about 1; about 1.2: about 1; about 1.1:about 1; or about 1: about 1.

Polyvinylpyrrolidione.

Another non-limiting example of a solubilizing agent ispolyvinylpyrrolidone (PVP), having the formula:

wherein the index n is from about 40 to about 200. PVP's can have anaverage molecular weight from about 5500 to about 28,000 g/mol. Onenon-limiting example is PVP-10, having an average molecular weight ofapproximately 10,000 g/mol.Polyakyleneoxides and Ethers Thereof.

Another non-limiting example of solubilizing agents includespolyalkyleneoxides, and polymers of alcohols or polyols. Polymers can bemixed, or contain a single monomeric repeat subunit. For example,polyethylene glycols having an average molecular weight of from about200 to about 20,000, for example, PEG 200, PEG 400, PEG 600, PEG 1000,PEG 1450, PEG 1500, PEG 4000, PEG 4600, and PEG 8000. In a sameembodiment, a composition comprises one or more polyethylene glycolschosen from PEG 400, PEG 1000, PEG 1450, PEG 4600 and PEG 8000.

Other polyalkyleneoxides are polypropylene glycols having the formula:HO[CH(CH₃)CH₂O]_(x)Hwherein the index x represents the average number of propyleneoxy unitsin the polymer. The index x can be represented by a whole number or afraction. For example, a polypropylene glycol having an averagemolecular weight of 8,000 g/mole (PEG 8000) can be represented by theformulae:HO[CH(CH₃)CH₂O]₁₃₈H or HO[CH(CH₃)CH₂O]_(137.6)Hor the polypropylene glycol can be represented by the common, short handnotation: PEG 8000.

Another example of polypropylene glycols can have an average molecularweight from about 1200 g/mol to about 20,000 g/mol, i.e., apolypropylene glycol having an average molecular weight of about 8,000g/mol, for example, PEG 8000.

Another solubilizing agent is Polysorbate 80 (Tween™ 80), which is anoleate ester of sorbitol and its anhydrides copolymerized withapproximately 20 moles of ethylene oxide for each mole of sorbitol andsorbitol anhydrides. Polysorbate 80 is made up of sorbitanmono-9-octadecanoate poly(oxy-1,2-ethandiyl) derivatives.

Solubilizing agents also include poloxamers having the formula:HO(CH₂CH₂)_(y1)(CH₂CH₂CH₂O)_(y2)(CH₂CH₂O)_(y3)OHwhich are nonionic block copolymers composed of a polypropyleneoxy unitflanked by two polyethyleneoxy units. The indices y¹, y², and y³ havevalues such that the poloxamer has an average molecular weight of fromabout 1000 g/mol to about 20,000 g/mol.

In some embodiments, a compound or pharmaceutically-acceptable saltthereof is present in a formulation in an amount of about 0.1 mg/mL toabout 100 mg/mL, about 0.1 mg/mL to about 1 mg/mL, about 0.1 mg/mL toabout 5 mg/mL, about 5 mg/mL to about 10 mg/mL, about 10 mg/mL to about15 mg/mL, about 15 mg/mL to about 20 mg/mL, about 20 mg/mL to about 25mg/mL, about 25 mg/mL to about 30 mg/mL, about 30 mg/mL to about 35mg/mL, about 35 mg/mL to about 40 mg/mL, about 40 mg/mL to about 45mg/mL, about 45 mg/mL to about 50 mg/mL, about 50 mg/mL to about 55mg/mL, about 55 mg/mL to about 60 mg/mL, about 60 mg/mL to about 65mg/mL, about 65 mg/mL to about 70 mg/mL, about 70 mg/mL to about 75mg/mL, about 75 mg/mL to about 80 mg/mL, about 80 mg/mL to about 85mg/mL, about 85 mg/mL to about 90 mg/mL, about 90 mg/mL to about 95mg/mL, or about 95 mg/mL to about 100 mg/mL.

In some embodiments, a compound or pharmaceutically-acceptable saltthereof is present in a formulation in an amount of about 1 mg/mL, about2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL,about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11mg/mL about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL,about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20mg/mL, about 21 mg/mL about 22 mg/mL, about 23 mg/mL, about 24 mg/mL,about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29mg/mL, about 30 mg/mL, about 31 mg/mL about 32 mg/mL, about 33 mg/mL,about 34 mg/mL, about 35 mg/mL, about 36 mg/mL, about 37 mg/mL, about 38mg/mL, about 39 mg/mL, about 40 mg/mL, about 41 mg/mL about 42 mg/mL,about 43 mg/mL, about 44 mg/mL, about 45 mg/mL, about 46 mg/mL, about 47mg/mL, about 48 mg/mL, about 49 mg/mL, about 50 mg/mL, about 51 mg/mLabout 52 mg/mL, about 53 mg/mL, about 54 mg/mL, about 55 mg/mL, about 56mg/mL, about 57 mg/mL, about 58 mg/mL, about 59 mg/mL, about 60 mg/mL,about 61 mg/mL about 62 mg/mL, about 63 mg/mL, about 64 mg/mL, about 65mg/mL, about 66 mg/mL, about 67 mg/mL, about 68 mg/mL, about 69 mg/mL,about 70 mg/mL, about 71 mg/mL about 72 mg/mL, about 73 mg/mL, about 74mg/mL, about 75 mg/mL, about 76 mg/mL, about 77 mg/mL, about 78 mg/mL,about 79 mg/mL, about 80 mg/mL, about 81 mg/mL about 82 mg/mL, about 83mg/mL, about 84 mg/mL, about 85 mg/mL, about 86 mg/mL, about 87 mg/mL,about 88 mg/mL, about 89 mg/mL, about 90 mg/mL, about 91 mg/mL about 92mg/mL, about 93 mg/mL, about 94 mg/mL, about 95 mg/mL, about 96 mg/mL,about 97 mg/mL, about 98 mg/mL, about 99 mg/mL, or about 100 mg/mL.

A formulation that is disclosed herein can be made more soluble by theaddition of an additive or agent. The improvement of solubility of theformulation can increase by about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about55%, about 60%, about 65%, about 70%, about 75% about 80%, about 85%,about 90%, about 95%, about 100%, about 110%, about 120%, about 130%,about 140%, about 150%, about 160%, about 170%, about 180%, about 190%,about 200%, about 225%, about 250%, about 275%, about 300%, about 325%,about 350%, about 375%, about 400%, about 450%, or about 500%.

A formulation disclosed herein can be stable for about 1 day, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 4weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks,about 3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, or about one year. A formulation disclosed herein can be stable,for example, at about 0° C., about 5° C., about 10° C., about 15° C.,about 20° C., about 25° C., about 30° C., about 35° C., about 40° C.,about 45° C., about 50° C., about 60° C., about 70° C., or about 80° C.

Excipients.

A pharmaceutical composition of the invention can be a combination ofany pharmaceutical compounds described herein with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. Pharmaceutical compositions can be administered intherapeutically-effective amounts as pharmaceutical compositions byvarious forms and routes including, for example, intravenous,subcutaneous, intramuscular, oral, rectal, aerosol, parenteral,ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topicaladministration.

A pharmaceutical composition can be administered in a local or systemicmanner, for example, via injection of the compound directly into anorgan, optionally in a depot or sustained release formulation.Pharmaceutical compositions can be provided in the form of a rapidrelease formulation, in the form of an extended release formulation, orin the form of an intermediate release formulation. A rapid release formcan provide an immediate release. An extended release formulation canprovide a controlled release or a sustained delayed release.

For oral administration, pharmaceutical compositions can be formulatedreadily by combining the active compounds withpharmaceutically-acceptable carriers or excipients. Such carriers can beused to formulate tablets, powders, pills, dragees, capsules, liquids,gels, syrups, elixirs, slurries, suspensions and the like, for oralingestion by a subject.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Cores can be provided with suitablecoatings. For this purpose, concentrated sugar solutions can be used,which can contain an excipient such as gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments can be added to the tablets or drageecoatings, for example, for identification or to characterize differentcombinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. In someembodiments, the capsule comprises a hard gelatin capsule comprising oneor more of pharmaceutical, bovine, and plant gelatins. A gelatin can bealkaline-processed. The push-fit capsules can contain the activeingredients in admixture with filler such as lactose, binders such asstarches, and/or lubricants such as talc or magnesium stearate and,stabilizers. In soft capsules, the active compounds can be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. Stabilizers can be added. All formulationsfor oral administration are provided in dosages suitable for suchadministration.

For buccal or sublingual administration, the compositions can betablets, lozenges, or gels.

Parenteral injections can be formulated for bolus injection orcontinuous infusion. The pharmaceutical compositions can be in a formsuitable for parenteral injection as a sterile suspension, solution oremulsion in oily or aqueous vehicles, and can contain formulatory agentssuch as suspending, stabilizing and/or dispersing agents. Pharmaceuticalformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form. Suspensions of the activecompounds can be prepared as oily injection suspensions. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions can contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. The suspension can also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The active compounds can be administered topically and can be formulatedinto a variety of topically administrable compositions, such assolutions, suspensions, lotions, gels, pastes, medicated sticks, balms,creams, and ointments. Such pharmaceutical compositions can containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

Formulations suitable for transdermal administration of the activecompounds can employ transdermal delivery devices and transdermaldelivery patches, and can be lipophilic emulsions or buffered aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches can be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical compounds. Transdermal delivery can beaccomplished by means of iontophoretic patches. Additionally,transdermal patches can provide controlled delivery. The rate ofabsorption can be slowed by using rate-controlling membranes or bytrapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices can be in the form of a bandage comprising a backing member, areservoir containing compounds and carriers, a rate controlling barrierto deliver the compounds to the skin of the subject at a controlled andpredetermined rate over a prolonged period of time, and adhesives tosecure the device to the skin or the eye.

For administration by inhalation, the active compounds can be in a formas an aerosol, a mist, or a powder. Pharmaceutical compositions areconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebuliser, with the use of a suitable propellant,for example, dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, for example, gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compounds and a suitablepowder base such as lactose or starch.

The compounds can also be formulated in rectal compositions such asenemas, rectal gels, rectal foams, rectal aerosols, suppositories, jellysuppositories, or retention enemas, containing conventional suppositorybases such as cocoa butter or other glycerides, as well as syntheticpolymers such as polyvinylpyrrolidone and PEG. In suppository forms ofthe compositions, a low-melting wax such as a mixture of fatty acidglycerides or cocoa butter can be used.

In practicing the methods of treatment or use provided herein,therapeutically-effective amounts of the compounds described herein areadministered in pharmaceutical compositions to a subject having adisease or condition to be treated. In some embodiments, the subject isa mammal such as a human. A therapeutically-effective amount can varywidely depending on the severity of the disease, the age and relativehealth of the subject, the potency of the compounds used, and otherfactors. The compounds can be used singly or in combination with one ormore therapeutic agents as components of mixtures.

Pharmaceutical compositions can be formulated using one or morephysiologically-acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active compounds intopreparations that can be used pharmaceutically. Formulation can bemodified depending upon the route of administration chosen.Pharmaceutical compositions comprising a compounds described herein canbe manufactured, for example, by mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orcompression processes.

The pharmaceutical compositions can include at least onepharmaceutically acceptable carrier, diluent, or excipient and compoundsdescribed herein as free-base or pharmaceutically-acceptable salt form.The methods and pharmaceutical compositions described herein include theuse crystalline forms (also known as polymorphs), and active metabolitesof these compounds having the same type of activity.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically-acceptable excipients or carriers to form asolid, semi-solid, or liquid composition. Solid compositions include,for example, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include, for example, solutionsin which a compound is dissolved, emulsions comprising a compound, or asolution containing liposomes, micelles, or nanoparticles comprising acompound as disclosed herein. Semi-solid compositions include, forexample, gels, suspensions and creams. The compositions can be in liquidsolutions or suspensions, solid forms suitable for solution orsuspension in a liquid prior to use, or as emulsions. These compositionscan also contain minor amounts of nontoxic, auxiliary substances, suchas wetting or emulsifying agents, pH buffering agents, and otherpharmaceutically-acceptable additives.

Non-limiting examples of dosage forms suitable for use in the inventioninclude feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant,spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension,nanoparticle, microgel, suppository troches, aqueous or oilysuspensions, ointment, patch, lotion, dentifrice, emulsion, creams,drops, dispersible powders or granules, emulsion in hard or soft gelcapsules, syrups, phytoceuticals, nutraceuticals, and any combinationthereof.

Non-limiting examples of pharmaceutically-acceptable excipients suitablefor use in the invention include granulating agents, binding agents,lubricating agents, disintegrating agents, sweetening agents, glidants,anti-adherents, anti-static agents, surfactants, anti-oxidants, gums,coating agents, coloring agents, flavouring agents, coating agents,plasticizers, preservatives, suspending agents, emulsifying agents,anti-microbial agents, plant cellulosic material and spheronizationagents, and any combination thereof.

A composition of the invention can be, for example, an immediate releaseform or a controlled release formulation. An immediate releaseformulation can be formulated to allow the compounds to act rapidly.Non-limiting examples of immediate release formulations include readilydissolvable formulations. A controlled release formulation can be apharmaceutical formulation that has been adapted such that drug releaserates and drug release profiles can be matched to physiological andchronotherapeutic requirements or, alternatively, has been formulated toeffect release of a drug at a programmed rate. Non-limiting examples ofcontrolled release formulations include granules, delayed releasegranules, hydrogels (e.g., of synthetic or natural origin), othergelling agents (e.g., gel-forming dietary fibers), matrix-basedformulations (e.g., formulations comprising a polymeric material havingat least one active ingredient dispersed through), granules within amatrix, polymeric mixtures, and granular masses.

The disclosed compositions can optionally comprise from about 0.001% toabout 0.005% weight by volume pharmaceutically acceptable preservatives.One non-limiting example of a suitable preservative is benzyl alcohol.

In some, a controlled release formulation is a delayed release form. Adelayed release form can be formulated to delay a compound's action foran extended period of time. A delayed release form can be formulated todelay the release of an effective dose of one or more compounds, forexample, for about 4, about 8, about 12, about 16, or about 24 hours.

A controlled release formulation can be a sustained release form. Asustained release form can be formulated to sustain, for example, thecompound's action over an extended period of time. A sustained releaseform can be formulated to provide an effective dose of any compounddescribed herein (e.g., provide a physiologically-effective bloodprofile) over about 4, about 8, about 12, about 16 or about 24 hours.

Non-limiting examples of pharmaceutically-acceptable excipients can befound, for example, in Remington: The Science and Practice of Pharmacy,Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), each of which is incorporated by reference in itsentirety.

The disclosed methods include administration of a HPTP-β inhibitor, or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier. The carrier can be selected tominimize any degradation of the active ingredient and to minimize anyadverse side effects in the subject.

In another aspect, the HPTP-β inhibitor or a pharmaceutically acceptablesalt thereof can be used prophylactically, i.e., as a preventative agentafter treatment with an anti-VEGF agent has stopped. The HPTP-βinhibitor or a pharmaceutically acceptable salt thereof herein can beconveniently formulated into pharmaceutical compositions composed of oneor more pharmaceutically acceptable carriers. See e.g., Remington'sPharmaceutical Sciences, latest edition, by E.W. Martin Mack Pub. Co.,Easton, Pa., which discloses typical carriers and conventional methodsof preparing pharmaceutical compositions that can be used in conjunctionwith the preparation of formulations of the compound described hereinand which is incorporated by reference herein. Such pharmaceuticals canbe standard carriers for administration of compositions to humans andnon-humans, including solutions such as sterile water, saline, andbuffered solutions at physiological pH. Other compositions can beadministered according to standard procedures. For example,pharmaceutical compositions can also include one or more additionalactive ingredients such as antimicrobial agents, anti-inflammatoryagents, and anesthetics.

Non-limiting examples of pharmaceutically-acceptable carriers include,but are not limited to, saline, Ringer's solution and dextrose solution.The pH of the solution can be from about 5 to about 8, and can be fromabout 7 to about 7.5. Further carriers include sustained releasepreparations such as semipermeable matrices of solid hydrophobicpolymers containing the HPTP-β inhibitor or apharmaceutically-acceptable salt thereof, where the matrices are in theform of shaped articles, e.g., films, liposomes, microparticles, ormicrocapsules.

The disclosed methods relate to administering the HPTP-β inhibitor or apharmaceutically acceptable salt thereof as part of a pharmaceuticalcomposition. In various embodiments, compositions of the invention cancomprise a liquid comprising an active agent in solution, in suspension,or both. Liquid compositions can include gels. In one embodiment, theliquid composition is aqueous. Alternatively, the composition can takeform of an ointment. In another embodiment, the composition is an insitu gellable aqueous composition. In some embodiments, the compositionis an in situ gellable aqueous solution. Such a composition can comprisea gelling agent in a concentration effective to promote gelling uponcontact with the eye or lacrimal fluid in the exterior of the eye.Aqueous compositions of the invention have ophthalmically compatible pHand osmolality. The composition can comprise an ophthalmic depotformulation comprising an active agent for subconjunctivaladministration. The microparticles comprising the active agent can beembedded in a biocompatible pharmaceutically acceptable polymer or alipid encapsulating agent. The depot formulations may be adapted torelease all or substantially all the active material over an extendedperiod of time. The polymer or lipid matrix, if present, may be adaptedto degrade sufficiently to be transported from the site ofadministration after release of all or substantially all of the activeagent. The depot formulation can be a liquid formulation, comprising apharmaceutically-acceptable polymer and a dissolved or dispersed activeagent. Upon injection, the polymer forms a depot at the injections site,e.g. by gelifying or precipitating. The composition can comprise a solidarticle that can be inserted in a suitable location in the eye, such asbetween the eye and eyelid or in the conjuctival sac, where the articlereleases the active agent. Solid articles suitable for implantation inthe eye can comprise polymers and can be bioerodible or non-bioerodible.

Pharmaceutical formulations can include additional carriers, as well asthickeners, diluents, buffers, preservatives, and surface active agentsin addition to the compounds disclosed herein. Pharmaceuticalformulations can also include one or more additional active ingredientssuch as antimicrobial agents, anti-inflammatory agents, anesthetics, andthe like.

An excipient can fill a role as simple and direct as being an inertfiller, or an excipient as used herein may be part of a pH stabilizingsystem or coating to insure delivery of the ingredients safely to thestomach.

The HPTP-β inhibitor or a pharmaceutically-acceptable salt thereof canalso be present in liquids, emulsions, or suspensions for delivery ofactive therapeutic agents in aerosol form to cavities of the body suchas the nose, throat, or bronchial passages. The ratio of HPTP-βinhibitor or a pharmaceutically-acceptable salt thereof to the othercompounding agents in these preparations can vary as the dosage formrequires.

Depending on the intended mode of administration, the pharmaceuticalcompositions administered as part of the disclosed methods can be in theform of solid, semi-solid or liquid dosage forms, such as, for example,tablets, suppositories, pills, capsules, powders, liquids, suspensions,lotions, creams, gels, or the like, for example, in unit dosage formsuitable for single administration of a precise dosage. The compositionscan contain, as noted above, an effective amount of the HPTP-β inhibitoror a pharmaceutically-acceptable salt thereof in combination with apharmaceutically-acceptable carrier and, in addition, can include othermedicinal agents, pharmaceutical agents, carriers, adjuvants, diluents,etc.

For solid compositions, nontoxic solid carriers include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talc, cellulose, glucose, sucrose, and magnesiumcarbonate. In one embodiment, a composition comprising the HPTP-βinhibitor or a pharmaceutically acceptable salt thereof in an amount ofapproximately 5 mg per 0.1 mL liquid is prepared. The liquid phasecomprises sterile water and an appropriate amount of a saccharide orpolysaccharide.

Methods of Administration and Treatment Methods.

Pharmaceutical compositions containing the compounds described hereincan be administered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions can be administered to asubject already suffering from a disease or condition, in an amountsufficient to cure or at least partially arrest the symptoms of thedisease or condition, or to cure, heal, improve, or ameliorate thecondition. Compounds can also be administered to lessen a likelihood ofdeveloping, contracting, or worsening a condition. Amounts effective forthis use can vary based on the severity and course of the disease orcondition, previous therapy, the subject's health status, weight,response to the drugs, and the judgment of the treating physician.

Multiple therapeutic agents can be administered in any order orsimultaneously. If simultaneously, the multiple therapeutic agents canbe provided in a single, unified form, or in multiple forms, forexample, as multiple separate pills. The compounds can be packedtogether or separately, in a single package or in a plurality ofpackages. One or all of the therapeutic agents can be given in multipledoses. If not simultaneous, the timing between the multiple doses mayvary.

Compounds and compositions of the invention can be packaged as a kit. Insome embodiments, the invention provides a kit comprising a compounddisclosed herein, or a pharmaceutically-acceptable salt thereof, andwritten instructions on use of the kit in the treatment of a conditiondescribed herein. In some embodiments, the invention provides a kitcomprising a compound disclosed herein, or a pharmaceutically-acceptablesalt thereof, an antibody, and written instructions on use of the kit inthe treatment of a condition described herein.

The compounds described herein can be administered before, during, orafter the occurrence of a disease or condition, and the timing ofadministering the composition containing a compound can vary. Forexample, the compounds can be used as a prophylactic and can beadministered continuously to subjects with a propensity to conditions ordiseases in order to lessen a likelihood of the occurrence of thedisease or condition. The compounds and compositions can be administeredto a subject during or as soon as possible after the onset of thesymptoms. The administration of the compounds can be initiated withinthe first 48 hours of the onset of the symptoms, within the first 24hours of the onset of the symptoms, within the first 6 hours of theonset of the symptoms, or within 3 hours of the onset of the symptoms.The initial administration can be via any route practical, such as byany route described herein using any formulation described herein. Acompound can be administered as soon as is practical after the onset ofa disease or condition is detected or suspected, and for a length oftime necessary for the treatment of the disease, such as, for example,from about 1 month to about 3 months. The length of treatment can varyfor each subject.

Pharmaceutical compositions described herein can be in unit dosage formssuitable for single administration of precise dosages. In unit dosageform, the formulation is divided into unit doses containing appropriatequantities of one or more compounds. The unit dosage can be in the formof a package containing discrete quantities of the formulation.Non-limiting examples are packaged injectables, vials, or ampoules.Aqueous suspension compositions can be packaged in single-dosenon-reclosable containers. Multiple-dose reclosable containers can beused, for example, in combination with or without a preservative.Formulations for parenteral injection can be presented in unit dosageform, for example, in ampoules, or in multi-dose containers with apreservative.

A compound described herein can be present in a composition in a rangeof from about 1 mg to about 2000 mg; from about 5 mg to about 1000 mg,from about 10 mg to about 25 mg to 500 mg, from about 50 mg to about 250mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg,from about 50 mg to about 100 mg, from about 100 mg to about 150 mg,from about 150 mg to about 200 mg, from about 200 mg to about 250 mg,from about 250 mg to about 300 mg, from about 300 mg to about 350 mg,from about 350 mg to about 400 mg, from about 400 mg to about 450 mg,from about 450 mg to about 500 mg, from about 500 mg to about 550 mg,from about 550 mg to about 600 mg, from about 600 mg to about 650 mg,from about 650 mg to about 700 mg, from about 700 mg to about 750 mg,from about 750 mg to about 800 mg, from about 800 mg to about 850 mg,from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, orfrom about 950 mg to about 1000 mg.

A compound described herein can be present in a composition in an amountof about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg,about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg,about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg,about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg,about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850mg, about 1900 mg, about 1950 mg, or about 2000 mg.

Methods.

Disclosed herein are methods for the treatment of diseases or conditionsof the eye, for example, diabetic macular edema, age-related maculardegeneration (including wet form), choroidal neovascularization,diabetic retinopathy, ocular ischemia, uveitis, retinal vein occlusion(central or branch), ocular trauma, surgery induced edema, surgeryinduced neovascularization, cystoid macular edema, ocular ischemia,changes in central foveal thickness, and uveitis. These diseases orconditions can be characterized by changes in the ocular vasculaturewhether progressive or non-progressive, whether a result of an acutedisease or condition, or a chronic disease or condition. In someembodiments, these diseases can be characterized by an increased levelof plasma Vascular Endothelial Growth Factor (VEGF).

In some embodiments, the disclosed methods relate to the administrationof the HPTP-β inhibitor or a pharmaceutically acceptable salt thereof,as well as compositions comprising the HPTP-β inhibitor or apharmaceutically-acceptable salt thereof.

In some embodiments, the methods of the disclosure are drawn towardsco-administration of a HPTP-β inhibitor or a pharmaceutically-acceptablesalt thereof which stabilizes the vasculature against leakage, and oneor more anti-VEGF agents.

In some embodiments, the methods of the disclosure are drawn towardsco-administration of a HPTP-β inhibitor or a pharmaceutically-acceptablesalt thereof which stabilizes the vasculature againstneovascularization, and one or more anti-VEGF agents.

In some embodiments, the inhibitor stabilizes the vasculature againstleakage and neovascularization.

In some embodiments, a human subject with at least one visually impairedeye is treated with an HPTP-β inhibitor or a pharmaceutically acceptablesalt thereof via subcutaneous or intravitreal injection. Improvement ofclinical symptoms can be monitored via, for example, indirectophthalmoscopy, fundus photography, fluorescein angiopathy,electroretinography, external eye examination, slit lamp biomicroscopy,applanation tonometry, pachymetry, optical coherence tomography andautorefaction. As described herein, the dosing can occur at anyfrequency determined by the administrator. After cessation of theanti-VEGF agent treatment, subsequent doses can be administered weeklyor monthly, e.g., with a frequency of 2-8 weeks or 1-12 months apartdepending upon the response.

One aspect of the disclosed methods relates to diseases that are adirect or indirect result of diabetes, inter alia, diabetic macularedema and diabetic retinopathy. The ocular vasculature of the diabeticbecomes unstable over time leading to conditions such asnon-proliferative retinopathy, macular edema, and proliferativeretinopathy. As fluid leaks into the center of the macula, the part ofthe eye where sharp, straight-ahead vision occurs, the buildup of fluidand the associated protein begin to deposit on or under the macula. Thisresults in swelling that causes the subject's central vision to becomedistorted. This condition is referred to as “macular edema.” Anothercondition that can occur is non-proliferative retinopathy in whichvascular changes, such as microaneurysms, outside the macular region ofthe eye can be observed.

These conditions can progress to diabetic proliferative retinopathy,which is characterized by increased neovascularization. These new bloodvessels are fragile and are susceptible to bleeding. The result isscarring of the retina, as well as occlusion or total blockage of thelight pathway through the eye due to the over formation of new bloodvessels. Diabetic macular edema can begin during either theproliferative or non-proliferative stage of diabetic retinopathy.

Diabetic retinopathy is a common cause of vision loss in working-agedAmericans. Severe vision loss can occur due to tractional retinaldetachments that complicate retinal neovascularization (NV), andmoderate vision loss can be caused by diabetic macular edema (DME). Thepathogenesis of DME can involve hypoxia. VEGF is a hypoxia-regulatedgene, and VEGF levels are increased in hypoxic or ischemic retina.Injection of VEGF into mouse eyes causes breakdown of the innerblood-retinal barrier and sustained release of VEGF in the eyes ofmonkeys causes macular edema.

The effects of VEGF on vascular endothelial cells are modulated by Tie2receptors, which are selectively expressed on vascular endothelial cellsand are required for embryonic vascular development. Angiopoietin 1(Ang1) binds Tie2 with high affinity and initiates phosphorylation anddownstream signaling. Angiopoietin 2 (Ang2) binds Tie2 with highaffinity, but does not stimulate phosphorylation in cultured endothelialcells. Ang2 acts as a competitive inhibitor of Ang1 and transgenic miceoverexpressing Ang2 have a phenotype similar to Ang1-deficient mice, andAng2 is a developmentally- and hypoxia-regulated permissive factor forVEGF-induced neovascularization in the retina. Ang2 reduces stabilizingsignals from the matrix making endothelial cells dependent upon VEGF andother soluble stimulators; when VEGF is high, neovascularization isstimulated and when VEGF is low, neovascularization regresses. Incontrast, Ang1 increases stabilizing signals from the matrix and makesthe vasculature unresponsive to soluble stimulators like VEGF.

Angiopoietin 2 binds Tie2, but does not stimulate phosphorylation andtherefore acts as an antagonist under most circumstances. In the eye,Ang2 is upregulated at sites of neovascularization and acts as apermissive factor for VEGF. Increased expression of VEGF in the retinadoes not stimulate sprouting of neovascularization from the superficialor intermediate capillary beds of the retina or the choriocapillaris,but does stimulate sprouting from the deep capillary bed. Co-expressionof VEGF and Ang2 at the surface of the retina causes sprouting ofneovascularization from the superficial retinal capillaries.

Macular degeneration is a condition characterized by a gradual loss orimpairment of eyesight due to cell and tissue degeneration of the yellowmacular region in the center of the retina. Macular degeneration isoften characterized as one of two types, non-exudative (dry form) orexudative (wet form). Although both types are bilateral and progressive,each type can reflect different pathological processes. The wet form ofage-related macular degeneration (AMD) is the most common form ofchoroidal neovascularization and a leading cause of blindness in theelderly. AMD affects millions of Americans over the age of 60, and is aleading cause of new blindness among the elderly.

Choroidal neovascular membrane (CNVM) is a problem that is related to awide variety of retinal diseases, and is commonly linked to AMD. WithCNVM, abnormal blood vessels stemming from the choroid (the bloodvessel-rich tissue layer just beneath the retina) grow up through theretinal layers. These new vessels are very fragile and break easily,causing blood and fluid to pool within the layers of the retina.

Diabetes (diabetes mellitus) is a metabolic disease caused by theinability of the pancreas to produce insulin or to use the insulin thatis produced. The most common types of diabetes are type 1 diabetes(often referred to as Juvenile Onset Diabetes Mellitus) and type 2diabetes (often referred to as Adult Onset Diabetes Mellitus). Type 1diabetes results from the body's failure to produce insulin due to lossof insulin producing cells, and presently requires the person to injectinsulin. Type 2 diabetes generally results from insulin resistance, acondition in which cells fail to use insulin properly.

Diabetes can be correlated to a large number of other conditions,including conditions or diseases of the eye including diabeticretinopathy (DR) and diabetic macular edema (DME), which are leadingcauses of vision loss and blindness in most developed countries. Theincreasing number of individuals with diabetes worldwide suggests thatDR and DME continue to be major contributors to vision loss andassociated functional impairment for years to come.

DR is a complication of diabetes that results from damage to the bloodvessels of the light-sensitive tissue at the back of the eye (retina).In early stages, DR frequently causes no symptoms or only mild visionproblems. Eventually, DR can result in blindness. DR can develop inanyone who has type 1 diabetes or type 2 diabetes.

At its earliest stage, non-proliferative retinopathy, microaneurysmsoccur in the retina's tiny blood vessels. As the disease progresses,more of these blood vessels become damaged or blocked and these areas ofthe retina send signals into the regional tissue to grow new bloodvessels for nourishment. This stage is called proliferative retinopathy.The new blood vessels grow along the retina and along the surface of theclear, vitreous gel that fills the inside of the eye. By themselves,these blood vessels do not cause symptoms or vision loss. However,without timely treatment, these new blood vessels can leak blood (wholeblood or some constituents thereof), resulting in severe vision loss andeven blindness. Also, fluid can leak into the center of the macula, thepart of the eye where sharp, straight-ahead vision occurs. The fluid andthe associated proteins begin to deposit on or under the macula, whichcauses the patient's central vision to become distorted. This conditionis called macular edema, and can occur at any stage of diabeticretinopathy, but is more likely to occur as the disease progresses.About half of the people with proliferative retinopathy also havemacular edema.

Uveitis is a condition in which the uvea becomes inflamed. The eye isshaped much like a tennis ball, hollow on the inside with threedifferent layers of tissue surrounding a central cavity. The outermostis the sclera (white coat of the eye) and the innermost is the retina.The middle layer between the sclera and the retina is called the uvea.The uvea contains many of the blood vessels that nourish the eye.Complications of uveitis include glaucoma, cataracts or new blood vesselformation (neovascularization).

Ocular trauma is any sort of physical or chemical injury to the eye.Symptoms include redness or pain in the affected eye.

Surgery-induced edema is the development of swelling in the eye tissuesfollowing surgery on the retina or other part of the eye. Cystoidmacular edema (CME) is an example of this phenomenon. CME can occur notonly in people who have had cataract surgery, but also those withdiabetes, retinitis pigmentosa, AMD, or conditions that cause chronicinflammation in the eye. Symptoms of CME include blurred or decreasedcentral vision.

Ocular ischemic syndrome (OIS) encompasses the signs and symptoms thatresult from chronic vascular insufficiency. This condition is caused byocular hypoperfusion due to occlusion or stenosis of the common orinternal carotid arteries. OIS generally affects those between the agesof 50-80, who can also have systemic diseases such as hypertension ordiabetes. Symptoms of OIS include orbital pain, vision loss, changes ofthe visual field, asymmetric cataract, and sluggish reaction to light.

Retinal vein occlusion (RVO) is the most common retinal vascular diseaseafter diabetic retinopathy. Depending on the area of retinal venousdrainage effectively occluded, the condition can be classified ascentral retinal vein occlusion (CRVO), hemispheric retinal veinocclusion (HRVO), or branch retinal vein occlusion (BRVO). Each type hastwo subtypes. Presentation of RVO is with variable painless visual losswith any combination of fundal findings consisting of retinal vasculartortuosity, retinal hemorrhages (blot and flame shaped), cotton woolspots, optic disc swelling, and macular edema. In a CRVO, retinalhemorrhages can be found in all four quadrants of the fundus, whereasthese are restricted to either the superior or inferior fundalhemisphere in a HRVO. In a BRVO, hemorrhages are largely localized tothe area drained by the occluded branch retinal vein. Vision loss occurssecondary to macular edema or ischemia.

Angiogenesis, the process of creating new blood vessels frompre-existing vessels, is essential to a wide range of physiological andpathological events including embryological development, menstruation,wound healing, and tumor growth. Most tumors require angiogenesis togrow and proliferate. VEGF is a major factor in angiogenesis, which canincrease vessel permeability and capillary number.

Vascular endothelial growth factor (VEGF) is a protein that is primarilyfound in endothelial cells and has functions in vasculogenesis,angiogenesis, and permeabilization of blood vessels. The expression ofVEGF is induced by hypoxia, activated oncogenes, and cytokines. VEGFactivation not only leads to angiogenesis in normal human cells andtissues, but also angiogenesis in tumors, allowing for tumor progressionand growth. Inhibition of VEGF inhibits tumor growth leading to tumorregression.

A variety of retinopathies are associated with increased levels of VEGF.Ischemia in the eye leads to an induction of VEGF production due to lackof oxygen. This increase in VEGF can cause hyperproliferation of bloodvessels in the retina, eventually leading to blindness. The disclosedHPTP-β inhibitors act to stabilize ocular vasculature and, in someembodiments, a compound of the invention can counteract the stimulationcaused by VEGF and other inflammatory agents that can be present in thediseased retina.

The compounds can be administered in any order convenient to the user orto the subject receiving treatment. In one non-limiting example of thedisclosed methods, a compound herein or a pharmaceutically acceptablesalt thereof is administered first followed by administration ofranibizumab. In another embodiment ranibizumab is administered firstfollowed by administration of the compound herein or a pharmaceuticallyacceptable salt thereof. The time period between dosing oradministration of the first component of treatment can be any timeperiod convenient to the formulator or subject receiving treatment. Forexample, the compound herein or a pharmaceutically acceptable saltthereof can be administered minutes, hours, days or weeks prior to theadministration of ranibizumab or more than one dosage of the compoundherein or a pharmaceutically acceptable salt thereof can be given toestablish a therapeutic amount in the subject being treated.

In a further embodiment, the compound herein or apharmaceutically-acceptable salt thereof are administered daily in oneor more doses and the ramibizumab is administered according to aseparate schedule. For example, in addition to daily dosing of thecompound herein, ranibizumab can be administered once a month, onceevery 2 months, once every 3 months, once every 4 months, once every 6months, etc.

The dosage for an antibody described herein can be in any amountnecessary. In one embodiment, the antibody is administered in an amountfrom about 0.05 mg to about 1.5 mg, from about 0.1 mg to about 1.5 mg,from about 0.1 to about 5 mg, from about 0.1 mg to about 3 mg, fromabout 0.5 mg to about 3 mg, or from about 0.5 mg to about 2 mg. In onenon-limiting example, the antibody is administered in an amount of 1.2mg. The amount of an antibody administered per treatment can be in anyamount, for example, about 0.05 mg, about 0.06 mg, about 0.07 mg, about0.08 mg, about 0.09 mg, about 0.1 mg, about 0.11 mg, about 0.12 mg,about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17,mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.21 mg, about0.22 mg, about 0.23 mg, about 0.24 mg, about 0.25 mg, about 0.26 mg,about 0.27, mg, about 0.28 mg, about 0.29 mg, about 0.3 mg, about 0.31mg, about 0.32 mg, about 0.33 mg, about 0.34 mg, about 0.35 mg, about0.36 mg, about 0.37, mg, about 0.38 mg, about 0.39 mg, about 0.4 mg,about 0.41 mg, about 0.42 mg, about 0.43 mg, about 0.44 mg, about 0.45mg, about 0.46 mg, about 0.47, mg, about 0.48 mg, about 0.49 mg, about0.5 mg, about 0.51 mg, about 0.52 mg, about 0.53 mg, about 0.54 mg,about 0.55 mg, about 0.56 mg, about 0.57, mg, about 0.58 mg, about 0.59mg, about 0.6 mg, about 0.61 mg, about 0.62 mg, about 0.63 mg, about0.64 mg, about 0.65 mg, about 0.66 mg, about 0.67, mg, about 0.68 mg,about 0.69 mg, about 0.7 mg, about 0.71 mg, about 0.72 mg, about 0.73mg, about 0.74 mg, about 0.75 mg, about 0.76 mg, about 0.77, mg, about0.78 mg, about 0.79 mg, about 0.8 mg, about 0.81 mg, about 0.82 mg,about 0.83 mg, about 0.84 mg, about 0.85 mg, about 0.86 mg, about 0.87,mg, about 0.88 mg, about 0.89 mg, about 0.9 mg, about 0.91 mg, about0.92 mg, about 0.93 mg, about 0.94 mg, about 0.95 mg, about 0.96 mg,about 0.97, mg, about 0.98 mg, about 0.99 mg, about 1 mg, about 1.01 mg,about 1.02 mg, about 1.03 mg, about 1.04 mg, about 1.05 mg, about 1.06mg, about 1.07, mg, about 1.08 mg, about 1.09 mg, 1.1 mg, about 1.11 mg,about 1.12 mg, about 1.13 mg, about 1.14 mg, about 1.15 mg, about 1.16mg, about 1.17, mg, about 1.18 mg, about 1.19 mg, about 1.2 mg, about1.21 mg, about 1.22 mg, about 1.23 mg, about 1.24 mg, about 1.25 mg,about 1.26 mg, about 1.27, mg, about 1.28 mg, about 1.29 mg, about 1.3mg, about 1.31 mg, about 1.32 mg, about 1.33 mg, about 1.34 mg, about1.35 mg, about 1.36 mg, about 1.37, mg, about 1.38 mg, about 1.39 mg,about 1.4 mg, about 1.41 mg, about 1.42 mg, about 1.43 mg, about 1.44mg, about 1.45 mg, about 1.46 mg, about 1.47, mg, about 1.48 mg, about1.49 mg, about 1.5 mg, about 1.51 mg, about 1.52 mg, about 1.53 mg,about 1.54 mg, about 1.55 mg, about 1.56 mg, about 1.57, mg, about 1.58mg, about 1.59 mg, about 1.6 mg, about 1.61 mg, about 1.62 mg, about1.63 mg, about 1.64 mg, about 1.65 mg, about 1.66 mg, about 1.67, mg,about 1.68 mg, about 1.69 mg, about 1.7 mg, about 1.71 mg, about 1.72mg, about 1.73 mg, about 1.74 mg, about 1.75 mg, about 1.76 mg, about1.77, mg, about 1.78 mg, about 1.79 mg, about 1.8 mg, about 1.81 mg,about 1.82 mg, about 1.83 mg, about 1.84 mg, about 1.85 mg, about 1.86mg, about 1.87, mg, about 1.88 mg, about 1.89 mg, about 1.9 mg, about1.91 mg, about 1.92 mg, about 1.93 mg, about 1.94 mg, about 1.95 mg,about 1.96 mg, about 1.97, mg, about 1.98 mg, about 1.99 mg, about 2 mg,about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg.

If the antibody is not administered simultaneously with the othercompound herein, then the time between administration of the compoundand the antibody can range, for example, from about 1 minute, about 2minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 2hours, about 3 hours, about 4 hours, about 5 hours, about 10 hours,about 20 hours, about 1 day, about 2 days, about 3 days, about 4 days,about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks,to about 4 weeks.

The HPTP-β inhibitors or a pharmaceutically-acceptable salt thereof canbe administered at any interval desired. For example, the compound canbe administered once a week, 2 times a week, 3 times a week, 4 times aweek, 5 times a week, 6 times a week, 7 times a week, 8 times a week, 9times a week, or 10 times a week. The interval between daily dosing canbe any hourly interval, for example, every hour, every 2 hours, every 3hours, every 4 hours, every 5 hours, every 6 hours, every 7 hours, every8 hours, every 9 hours, every 10 hours, every 11 hours, or every 12hours.

Further non-limiting examples of anti-VEGF agents include dexamethasone,fluocinolone and triamcinolone. The disclosed methods can includeimplants that deliver an anti-VEGF agent. For example, HPTP-β inhibitorsor a pharmaceutically-acceptable salt thereof can be co-administeredbefore, during, or after an implant is provided to a subject sufferingfrom a disease or condition described herein. For example, Ozurdex™ isan intraviteal implant that provides a supply of dexamethasone to asubject, Retisert™ and Iluvien™ are intravitreal implants that provide asupply of fluocinolone.

In some embodiments, a subject's Central Foveal Thickness is decreasedfrom about 50 μm to about 1000 μm, from about 50 μm to about 750 μm,from about 200 μm to about 1000 μm, from about 150 μm to about 500 μm,from about 50 μm to about 500 μm, from about 250 μm to about 650 μm,from about 200 μm to about 500 μm, or from about 400 μm to about 700 μm.

Visual Acuity.

Further disclosed herein are methods for increasing the visual acuity ofa subject having a disease or condition as disclosed herein. Visualacuity (VA) is acuteness or clearness of vision, which is dependent onthe sharpness of the retinal focus within the eye and the sensitivity ofthe interpretative faculty of the brain. Visual acuity is a measure ofthe spatial resolution of the visual processing system. VA is tested byrequiring the person whose vision is being tested to identifycharacters, typically numbers or letters, on a chart from a setdistance. Chart characters are represented as black symbols against awhite background. The distance between the person's eyes and the testingchart is set at a sufficient distance to approximate infinity in the waythe lens attempts to focus. Twenty feet, or six meters, is essentiallyinfinity from an optical perspective.

EXAMPLES Example 1: Synthesis of an HPTP-Beta Inhibitor and itsDiastereomers

Four compounds (A, B, C, and D) are shown below. Compound A is the S,Rconfiguration; Compound B is the R,S configuration; Compound C is theR,R configuration; Compound D is the S, S configuration.

The generalized reaction scheme below was used to synthesize thecompounds.

Synthesis of the starting material compound 51 for the synthesis of thecompounds is detailed below:

The R-isomer of compound S1 was prepared by adding compound S1-2 (5.7mL, 44 mmol, 1.1 eq) dropwise at 0° C. to a solution of compound S1-1(12 g, 38.7 mmol, 1.0 eq) and Et₃N (6.1 mL, d=0.75 g/mL, 44 mmol, 1.1eq). After the addition, the mixture was stirred for another 1.5 h at 0°C. TLC analysis indicated that compound S1-1 was almost consumed. Thereaction was stopped at that point and the reaction mixture wasfiltered. The filtrate was treated with CH₂N₂ at 0° C. for 30 min toproduce the diazomethyl ketone. The reaction mixture became dark brownat that point. 40% HBr aqueous solution was then slowly added dropwiseat 0° C. and the reaction mixture was stirred for 30 min A saturatedNa₂CO₃ solution was added to adjust the pH to 7-8. The mixture wasextracted with EtOAc, dried and concentrated to give S1 (14.9 g). H-NMRanalysis showed 74% of S1 and 26% of methyl ester as shown in FIG. 16.HPLC analysis showed 78.2% purity as shown in FIG. 17. The mixture wasused for next step directly. For the intermediates used to synthesizecompounds B, and C, only the analytical data are provided in lattersections as the intermediates were synthesized using the same procedureused for compound A.

Step 1 of the pathway to synthesize compound A is detailed in thereaction scheme below:

Synthesis of compound 1 was performed using a solution of compound S1(10 g, 25.8 mmol 1.0 eq) and compound S2 (3.88 g, 27.0 mmol, 1.05 eq) inCH₃CN (200 mL) at reflux for 3 h. TLC analysis indicated that compoundS1 was consumed. The reaction mixture was then cooled to roomtemperature. The solid was collected by filtration and dried under highvacuum. 10.2 g of 1 was obtained as a white solid. The yield was 96%.

The analytical data for compound 1 were as follows: HPLC: ˜100% (FIG.2); LCMS (ESI+): m/z 332 (M+H) (FIG. 3); ¹H-NMR (300 MHz, DMSO-d₆) δ8.52 (br s, 3H), 8.15 (d, J=8.6 Hz, 2H), 7.77 (d, J=4.2 Hz, 1H), 7.70(d, J=3.6 Hz, 1H), 7.57 (s, 1H), 7.18 (dd, J=4.2 Hz, J=3.6 Hz, 1H), 4.85(t, J=7.4 Hz, 1H), 3.40 (d, J=7.4 Hz, 2H) (FIG. 1).

Step 2 of the scheme is detailed below.

Synthesis of compound 2 was done by charging a 100 mL three-neckedround-bottom flask with compound S3 (3 g, 18.2 mmol, 1.0 eq), THF (60mL), water (60 mL) and NaHCO₃ (2.3 g, 27.4 mmol, 1.5 eq). The resultingslurry was cooled to 5° C. Methyl chloroformate (MCF) (2.0 g, 21.3 mmol,1.2 eq) was added dropwise over 5 minutes and the resulting mixture wasstirred at RT overnight. The pH of the reaction mixture was thenadjusted to <2 by the addition of the concentrated HCl (˜15 mL). Thequenched reaction mixture was extracted with EtOAc (3×50 mL). Thecombined organic layer was washed with brine (3×100 mL), dried overMgSO₄, filtered and concentrated to give the crude product of compound 2(4.3 g, yield >100%). Compound 2 was directly used for the next stepwithout further purification.

Step 3 of the scheme is detailed below.

Synthesis for compound 3 was done by adding1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (4.8 g, 27.2 mmol,1.1 eq), followed by DIPEA (8.7 g, 4.28 g, 3 eq) to a solution ofcompound 1 (10.2 g, 24.7 mmol, 1.0 eq), compound 2 (5.53 g, 24.8 mmol, 1eq), and 1-hydroxybenzotriazole (HOBt) (5.0 g, 41.6 mmol, 1.7 eq) in amixture of DMF (70 mL) and MTBE (25 mL) at 0° C. The resulting mixturewas stirred at 0° C. for 30 minutes, then allowed to warm to RT andstirred overnight. TLC analysis indicated that compound 1 was consumed.The reaction mixture was diluted with water (200 mL) and extracted withEtOAc (3×300 mL). The combined organic phase was washed with a dilutedaqueous HCl solution (1 N, 200 mL), 5% aqueous NaHCO₃ (200 mL), water(200 mL) and brine (200 mL). The organic layer was then dried overNa₂SO₄ and concentrated to give 10 g of compound 3 as yellow solid. Theyield was 75%. The crude product of compound 3 was directly used for thenext step without further purification.

The analytical data for compound 3 were as follows: HPLC: 97% (FIG. 5);LCMS (ESI+): m/z 537 (M+H) (FIG. 6); ¹H-NMR (300 MHz, DMSO-d₆) δ 8.72(d, J=8.7 Hz, 1H), 8.12 (d, J=8.7 Hz, 2H), 7.73 (dd, J=0.9 Hz, 5.1 Hz,1H), 7.67 (dd, J=0.9 Hz, 5.1 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.43 (s,1H), 7.32 (d, J=8.7 Hz, 1H), 7.25-7.10 (m, 6H), 5.23-5.31 (m, 1H),4.16-4.23 (m, 1H), 3.41 (s, 3H), 3.34-3.37 (m, 1H), 3.11-3.19 (m, 1H),2.61-2.66 (m, 1H), 2.49-2.53 (m, 1H) (FIG. 4).

Step 4 of the scheme is detailed below.

Synthesis for compound 4 was done by adding FeCl₃ (0.6 g, 3.7 mmol, 0.2eq) and charcoal (4.0 g) to a solution of compound 3 (10 g, 18.7 mmol,1.0 eq) in EtOH (400 mL). The mixture was heated to reflux and hydrazinehydrate (30.0 g, 600 mmol, 32.0 eq) was added. The reaction mixture washeated at reflux until compound 3 was completely consumed as indicatedby TLC (˜2 h). The charcoal and the inorganic salts were filtered offthrough a pad of Celite, and the Celite was washed with EtOH. Thefiltrate was concentrated to give 9.3 g of a crude product of compound 4(yield 98.9%) as a white solid, which was directly used for the nextstep without further purification.

The analytical data for compound 4 were as follows: HPLC: 96% (FIG. 7);LCMS (ESI+): m/z 507 (M+H) (FIG. 8); ¹H-NMR (300 MHz, DMSO-d₆) δ 8.54(d, J=8.7 Hz, 1H), 7.73 (d, J=4.8 Hz, 1H), 7.66 (d, J=3.6 Hz, 1H),7.15-7.32 (m, 8H), 6.89 (d, J=8.1 Hz, 2H), 6.43 (d, J=8.1 Hz, 2H),4.89-5.05 (m, 1H), 4.84 (s, 2H), 4.19-4.24 (m, 1H), 3.41 (s, 3H),2.99-3.06 (m, 1H), 2.68-2.83 (m, 2H), 2.54-2.58 (m, 1H) (FIG. 9).

Step 5 of the scheme is detailed below.

To create compound 5 Me₃NSO₃ (1.65 g, 11.9 mmol, 1.5 eq) and then NMM(1.45 g, 14.4 mmol, 1.8 eq) were added to a solution of compound 4 (4.0g, 7.9 mmol, 1.0 eq) in dry THF (100 mL) at RT. The resulting mixturewas heated to reflux and stirred overnight. TLC analysis of the reactionmixture indicated that compound 4 was not completely consumed. Thereaction was stopped at that point. The reaction mixture wasconcentrated to dryness to afford the crude product of compound 5. Thecrude product of compound 5 was purified by flash column chromatographyto give compound 5 (3.3 g, yield 71.7%) as a white solid containingtraces of residual ethyl acetate.

The analytical data for compound 5 were as follows: HPLC: 99.6% (FIG.10); LCMS (ESI⁻): m/z 585 (M−H) (FIG. 11); ¹H-NMR (300 MHz, DMSO-d₆) δ8.47 (d, J=8.7 Hz, 1H), 7.72 (d, J=4.5 Hz, 1H), 7.66 (d, J=3.6 Hz, 1H),7.24-7.33 (m, 6H), 7.16-7.20 (m, 2H), 6.90 (s, 4H), 5.06-5.08 (m, 1H),4.20-4.26 (m, 1H), 3.42 (s, 3H), 3.02-3.09 (m, 2H), 2.86-2.91 (m, 1H),2.76-2.83 (m, 2H), 2.61-2.65 (m, 1H) (FIG. 12).

Step 6 of the scheme is detailed below.

To create compound A an aqueous solution of NaOH (164 mg in 245 mg ofH₂O, 4.1 mmol, 1.2 eq) was added dropwise at RT over 5 min to a solutionof compound 5 (2.0 g, 3.4 mmol, 1.0 eq) in MeOH (20 mL) and theresulting reaction mixture was stirred at RT for 2 h. The solid productwas collected by vacuum filtration, washed with EtOAc (100 mL), and thenEt₂O (100 mL). 1.0 g of compound A was obtained as white solid. Theyield was 48.3%.

Analytical data for compound A were as follows: HPLC: ˜100% (FIG. 13);LCMS (ESI+): m/z 587 (M−Na+2H) (FIG. 14); ¹H-NMR (300 MHz, DMSO-d₆) δ8.47 (d, J=8.4 Hz, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.63-7.66 (m, 2H),7.16-7.33 (m, 8H), 6.90 (s, 4H), 5.03-5.08 (m, 1H), 4.21-4.26 (m, 1H),3.42 (s, 3H), 3.03-3.09 (m, 1H), 2.77-2.91 (m, 2H), 2.57-2.65 (m, 1H)(FIG. 15).

Step 1 of the pathway to synthesize compound C is detailed in thereaction scheme below:

To create compound 1 a solution of compound S1 (14.9 g, ˜74% purity,counted as 11 g of 51, 28.4 mmol, 1.0 eq) and compound S2 (4.1 g, 29.8mmol, 1.05 eq) in CH₃CN (300 mL) was heated at reflux for 5 h. TLCanalysis indicated that compound S1 was almost consumed. The reactionmixture was cooled to RT. The resulting solid was collected by vacuumfiltration to provide 7.8 g of the crude product of compound 1.

The analytical data for compound 1 were as follows: HPLC: 97.5% (FIG.18); ¹H-NMR (300 MHz, CD₃OD) δ 8.17 (d, J=8.7 Hz, 2H), 7.63 (d, J=5.1Hz, 2H), 7.43 (d, J=3.7 Hz, 2H), 7.33 (s, 1H), 7.16 (d, J=8.7 Hz, 1H),4.84 (s, 1H), 3.58-3.43 (m, 2H) (FIG. 19).

Step 3 of the scheme is detailed below. Compound 3 was synthesized usingthe same procedure for step 3 for the synthesis of compound A.

The analytical data for compound 3 were as follows: HPLC: 97.8% (FIG.20); LCMS (ESI+): m/z 537 (M+H) (FIG. 21); ¹H-NMR (300 MHz, CDCl₃) δ8.07 (d, J=8.5 Hz, 2H), 7.51 (d, J=3.4 Hz, 1H), 7.45 (d, J=5.0 Hz, 1H),7.19 (d, J=8.5 Hz, 2H), 7.15-7.08 (m, 4H), 7.06-6.98 (m, 1H), 6.54 (s,1H), 6.45-6.35 (m, 1H), 5.32-5.21 (m, 2H), 4.42-4.30 (m, 1H), 3.68 (s,3H), 3.32-3.20 (m, 1H), 3.18-3.02 (m, 1H), 2.98-2.85 (m, 1H) (FIG. 22).

Step 4 of the scheme is detailed below. Compound 4 was synthesized usingthe same procedure for step 4 for the synthesis of compound A.

The analytical data for compound 4 were as follows: HPLC: 95.9% (FIG.23); LCMS (ESI+): m/z 507 (M+H) (FIG. 24); ¹H-NMR (300 MHz, DMSO-d₆) δ8.44 (d, J=8.4 Hz, 1H), 7.70 (d, J=5.0 Hz, 1H), 7.63 (d, J=3.6 Hz, 1H),7.32 (d, J=8.1 Hz, 1H), 7.26-7.18 (m, 4H), 7.20-7.11 (m, 2H), 7.03 (s,1H), 6.84 (d, J=8.2 Hz, 2H), 6.43 (d, J=8.2 Hz, 2H), 5.10-4.92 (m, 1H),4.35-4.21 (m, 1H), 3.45 (s, 3H), 3.08-2.93 (m, 1H), 2.90-2.78 (m, 2H),2.75-2.64 (m, 1H) (FIG. 25).

Step 5 of the scheme is detailed below. Compound 5 was synthesized usingthe same procedure for step 5 for the synthesis of compound A.

The analytical data for compound 5 were as follows: HPLC: 96.9% (FIG.26); LCMS (ESI−): m/z 585 (M−H) (FIG. 27); ¹H-NMR (300 MHz, DMSO-d₆) δ8.46 (d, J=8.3 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J=5.0 Hz, 1H), 7.63 (d,J=3.0 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.28-7.15 (m, 4H), 7.18-7.12 (m,2H), 7.03 (s, 1H), 6.90 (s, 4H), 5.14-5.02 (m, 1H), 4.35-4.22 (m, 1H),3.46 (s, 3H), 3.13-3.01 (m, 1H), 2.98-2.88 (m, 2H), 2.75-2.64 (m, 1H)(FIG. 28).

Step 6 of the scheme is detailed below. Compound C was synthesized usingthe same procedure as described for compound A.

The analytical data for compound C were as follows: HPLC: 98.7% (FIG.29); LCMS (ESI+): m/z 587 (M−Na+2H) (FIG. 30); ¹H-NMR (300 MHz, DMSO-d₆)δ 8.46 (d, J=8.0 Hz, 1H), 7.75-7.61 (m, 3H), 7.36 (d, J=8.7 Hz, 1H),7.28-7.12 (m, 6H), 7.03 (s, 1H), 6.87 (s, 4H), 5.05 (m, 1H), 4.27 (m,1H), 3.46 (s, 3H), 3.10-3.01 (m, 1H), 3.10-2.85 (m, 2H), 2.82-2.65 (m,1H) (FIG. 31).

Step 3 of the reaction used to create compound B is detailed in thereaction scheme shown below. Compound 3 was synthesized using the sameprocedure for step 3 for the synthesis of compound A.

The analytical data for Compound 3, as shown above, were as follows:HPLC: 97.3% (FIG. 32); LCMS (ESI+): m/z 537 (M+H) (FIG. 33); ¹H-NMR (300MHz, DMSO-d₆) δ 8.68 (d, J=8.7 Hz, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.73 (d,J=4.3 Hz, 1H), 7.67 (d, J=3.6 Hz, 1H), 7.52 (d, J=8.6 Hz, 2H), 7.42 (s,1H), 7.30-7.11 (m, 7H), 5.35-5.18 (m, 1H), 4.28-4.14 (m, 1H), 3.42 (s,3H), 3.39-3.32 (m, 1H), 3.22-3.08 (m, 1H), 2.71-2.53 (m, 2H) (FIG. 34).

Step 4 of the reaction used to create compound B is detailed in thereaction scheme below. Compound 4 was synthesized using the sameprocedure for step 4 for the synthesis of compound A.

The analytical data for compound 4 were as follows: HPLC: 98.3% (FIG.35); LCMS (ESI+): m/z 507 (M+H) (FIG. 36); ¹H-NMR (300 MHz, DMSO-d₆) δ8.46 (d, J=8.5 Hz, 1H), 7.72 (d, J=4.1 Hz, 1H), 7.66 (d, J=3.63 Hz, 1H),7.38-7.15 (m, 8H), 6.89 (d, J=8.3 Hz, 2H), 6.44 (d, J=8.3 Hz, 2H),5.11-4.98 (m, 1H), 4.28-4.21 (m, 1H), 3.42 (s, 3H), 3.08-2.98 (m, 1H),2.88-2.72 (m, 2H), 2.66-2.57 (m, 1H) (FIG. 37).

Step 5 of the reaction used to create compound B is detailed in thereaction scheme below. Compound 5 was synthesized using the sameprocedure for step 5 for the synthesis of compound A.

The analytical data for compound 5, as shown above, were as follows:HPLC: 96.1% (FIG. 38); LCMS (ESI+): m/z 507 (M−S03+H) (FIG. 39); ¹H-NMR(300 MHz, DMSO-d₆) δ 8.47 (d, J=8.5 Hz, 1H), 7.72 (d, J=4.9 Hz, 1H),7.66 (d, J=3.5 Hz, 2H), 7.32-7.22 (m, 6H), 7.23-7.12 (m, 2H), 6.96 (s,4H), 5.15-5.01 (m, 1H), 4.32-4.20 (m, 1H), 3.42 (s, 3H), 3.12-3.03 (m,1H), 2.93-2.85 (m, 1H), 2.83-2.76 (m, 1H), 2.68-2.56 (m, 1H) (FIG. 40).

Step 6 of the pathway used to synthesize compound B is detailed in thereaction scheme below. Compound B was synthesized using the sameprocedure as described for compound A.

The analytical data for compound B were as follows: HPLC: 97% (FIG. 41);LCMS (ESI+): m/z 587 (M−Na+2H) (FIG. 42); ¹H-NMR (300 MHz, DMSO-d₆) δ8.46 (d, J=8.1 Hz, 1H), 7.72 (d, J=4.4 Hz, 1H), 7.68-759 (m, 2H),7.38-7.12 (m, 8H), 6.89 (s, 4H), 5.14-5.02 (m, 1H), 4.28-4.18 (m, 1H),3.42 (s, 3H), 3.11-3.01 (m, 1H), 2.96-2.75 (m, 2H), 2.70-2.55 (m, 1H)(FIG. 43).

The complete reaction scheme for the synthesis of compound B is detailedbelow:

Example 2: Tie2 Activation and Downstream Phosphorylation of Akt inCultured Endothelial Cells

A cell-based assay of compounds A-D is described herein.

Human umbilical vein endothelial cells (HUVECs) were isolated freshlyfrom human placenta, grown in endothelial growth medium, and used beforepassage 6. To evaluate the effects of the compounds on phosphorylationof Tie2 and downstream signaling molecules, cells were serum-starved inendothelial basal medium without added growth factors for 3 hours beforestimulation. Cells were treated for 10 minutes with vehicle (DMSO), orcompounds A, B, C, or D in DMSO. Cells were lysed in RIPA buffer (150 mMNaCl, 1% IGEPAL CA-630, 0.05% sodium deoxycholate, 0.1% SDS, 20 mMTris-HCl at pH 7.6, 1 mM EDTA, 1 mM NaF, 1 mM sodium orthovanadate, 5 mMbenzamidine) plus complete protease inhibitor cocktail tablets. Tie2 wasthen immunoprecipitated from cell lysates with a mouse monoclonalantibody (clone 33) and probed sequentially with mouse monoclonalanti-phosphotyrosine (clone 4G10) and anti-Tie2 (clone 33). Whole celllysates were used to quantify phospho-AKT with the PathScan Phospho-Akt1(Ser473) Sandwich ELISA Kit according to the manufacturer'sinstructions. Relative AKT phosphorylation in each experiment wasquantified by OD₄₅₀.

FIG. 44 is a western blot of Tie2 immunoprecipitated from endothelialcells treated with DMSO control or the indicated compounds (D, C, B, orA), and then sequentially probed with an anti-Tie2 antibody to detecttotal Tie2 (lower blot) and an anti-phosphotyrosine antibody to detectphosphorylated Tie2 (upper blot). The blot shows that Tie2 wasimmunoprecipitated at relatively equal amounts, whereas Tie2phosphorylation differed between the treatment conditions. Treatmentwith compound D resulted in a substantial increase in Tie2phosphorylation compared to the DMSO control. An increase in Tie2phosphorylation compared to the DMSO control was not detected forcompounds A, B, and C.

FIG. 45 represents data from an ELISA to determine Akt phosphorylation,a measure of Tie2 activation. Consistent with FIG. 44, compound D hadthe strongest effect on Tie2 activation, as determined by the highlevels (OD₄₅₀=1.2) of relative Akt phosphorylation even at the lowestdose of compound D (1 μg/mL). Akt phosphorylation significantlyincreased (OD₄₅₀=3.1) using compound D at 3 μg/mL reaching a maximum ofAkt phosphorylation, which did not increase further at the highest doseof compound D (10 μg/mL). Compound A had a moderate effect on Aktphosphorylation and began to show effects at 3 μg/mL, where Aktphosphorylation slightly increased (OD₄₅₀=0.2). Akt phosphorylationfurther increased (OD₄₅₀=0.45) when 10 μg/mL of compound A was used.Compounds B and C had similar effects on Akt phosphorylation, moderatelyincreasing Akt phosphorylation (OD₄₅₀ around 0.2) most significantlywhen used at 10 μg/mL.

Example 3: Formulation of Compound with HPβCD

Compositions of any of compounds A, B, C, and D are prepared by dilutingabout 100 mg of a sterile powder of a compound in 100 mL water to form afirst composition. To the first composition is added 250 mg ofhydroxypropyl beta cyclodextrin (HPβCD). Example compositions are shownin TABLE I.

TABLE I Compound (mg) HPβCD (mg) Water (mL) 50 250 25 50 250 50 50 25075 50 250 100 100 250 25 100 250 50 100 250 75 100 250 100 50 250 200 50250 300 50 250 400 50 250 500 100 250 200 100 250 300 100 250 400 100250 500

Example 4: Formulation of Compound with HPβCD

To a 100 mL volumetric flask containing water (85 mL) were charged HPβCD(10 g) and dextrose (1.5 g). The solution was stirred for 1 hour at 20°C., then the volume made up to 100 mL with additional distilled water.The resulting solution was 10% HPβCD and 1.5% dextrose.

In a similar manner, solutions comprising 15% HPβCD/1.5% dextrose and17.5% HPβCD/1.5% dextrose were prepared. These stock solutions were usedfor the following experiments.

In a 25 mL volumetric flask was added the stock solution comprising 10%HPβCD/1.5% dextrose followed by the addition of the sodium salt ofcompound D (550 mg). The total volume was made up to 25 mL by theaddition of distilled water. The resulting solution had a nominalconcentration of compound D of 20 mg/mL after applying a molecularweight correction factor.

Similarly, to a stock solution comprising 10% HPβCD/1.5% dextrose wasadded compound D (687 mg). After dilution to 25 mL the resultingsolution had a nominal concentration of compound D of 25 mg/mL afterapplying a molecular weight correction factor.

Compositions comprising 15% HPβCD/1.5% dextrose and 687 mg and 825 mg ofcompound D were also prepared. Likewise, compositions comprising 17.5%HPβCD/1.5% dextrose and 825 mg and 962.5 mg of the sodium salt ofcompound D were also prepared.

TABLE II describes the test compositions, each totaling 25 mL.

TABLE II 10% 15% 17.5% Stock HPβCD/ HPβCD/ HPβCD/ Solution 1.5% dex.1.5% dex. 1.5% dex. Comp 550 687 687 825 825 962.5 D-Na (mg) Comp D 2025 25 30 30 35 mg/mL

To 3 one-dram vials was transferred approximately 3 mL of each of the 6solutions above. One vial of each solution was held at 4° C., 20° C. and40° C. The vials were evaluated weekly for one month then monthly forthree months.

After 3 months none of the vials appeared hazy or had any precipitate orflocculent. The above compositions where then further processed andsubmitted for in vivo testing.

Example 5: Preparation of Compositions for Subcutaneous Delivery Via0.75 mL Single Use Syringes

200 mL of deionized water is added to 2-hydroxypropyl-β-cyclodextrin (50g) with stirring. Next, dextrose (96%) (1.3 g) is added, and thesolution is stirred until all the solids are dissolved. A formulationcontaining one of the compounds disclosed herein or a mixture thereof isadded, and the solution is stirred until the solids are dissolved. Theresulting solution has a pH value of 7.26 and a density of 1.07 g/mL.The final solution is filtered through a 20-0.22 micron PVDF filter. Acalibrated peristaltic pump is used to dispense 0.75 mL of the finalsolution into 0.75 mL syringes having 27 g staked needles and stoppers.

Example 6: Preparation of Compositions for Subcutaneous Delivery Via0.75 mL Single Use Syringes

200 mL of deionized water is added to 2-hydroxypropyl-β-cyclodextrin(43.75 g) with stirring. Next, dextrose (96%) (2.61 g) is added and thesolution is stirred until all the solids are dissolved. A formulationcontaining one of the compounds disclosed herein or a mixture thereof isadded, and the solution is stirred until the solids are dissolved. Theresulting solution has a pH value of 7.32, which is adjusted to 7.04with 1N HCl (0.5 mL). The final solution is filtered through a 20-0.22micron PVDF filter. A calibrated peristaltic pump is used to dispense0.75 mL of the final solution into 0.75 mL syringes having 27 g stakedneedles and stoppers.

Example 7: Preparation of Compositions for Subcutaneous Delivery Via0.75 mL Single Use Syringes

200 mL of deionized water is added to 2-hydroxypropyl-β-cyclodextrin(56.25 g) with stirring. Next, dextrose (96%) (1.3 g) is added and thesolution is stirred until all the solids are dissolved. A formulationcontaining one of the compounds disclosed herein or a mixture thereof isadded, and the solution is stirred until the solids are dissolved. Thefinal solution is filtered through a 20-0.22 micron PVDF filter. Acalibrated peristaltic pump is used to dispense 0.75 mL of the finalsolution into 0.75 mL syringes having 27 g staked needles and stoppers.

Example 8: Step-Wise Manufacturing Process: 20 mg of Compound D Per mLSolution

1. Add approximately 16.0 kg of United States Pharmacopeia (USP) SterileWater for Injection to an appropriately-sized glass vessel.

2. Add 2812.5 g of 2-hydroxylpropyl-beta-cyclodextrin (HPβCD) (USP) tothe glass flask and mix for a minimum of 5 minutes or until dissolved.

3. Add 450 g of compound D, as the sodium salt, factored for purity,minor stereoisomers, volatiles and water, to the glass flask and mix fora minimum of 30 minutes or until all of the solids are dissolved.

4. Add 450 g of D-glucose (Dextrose) Anhydrous (USP) to the glass flaskand mix for a minimum of 5 minutes or until all of the solids aredissolved.

5. Transfer the solution to a 36 L glass formulation vessel using aperistaltic pump.

6. QS the formulation to 22.7 kg by adding Sterile Water for Injection,USP and mix for a minimum of 30 minutes or until dissolved.

7. Adjust the pH to obtain a pH of 6.6-7.0.

8. Add sufficient quantities of Sterile Water for Injection, USP to thebatch to obtain the final batch weight of 23.7 kg (22.5 L*1.052g/mL—specific gravity) and mix for a minimum of 10 minutes or until allof the solids are dissolved.

9. Filter through two filters connected in series into a similar 36 Lglass fill vessel.

10. Fill into various syringes: i.e., 0.75 mL syringe.

Example 9: Baseline Study for Determining the Effectiveness of theDisclosed Methods for Treating Ocular Diseases

Described herein is a study of four human subjects with visual acuityloss due to diabetic macular edema (central retinal thickness [CRT] ofmore than 325 microns and best corrected visual acuity less than 70letters) that were treated with subcutaneous injections of 5 mg of4-{(S)-2-[(S)-2-methoxycarbonyl-amino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid twice a day for 28 days. Improvement of visual acuity in thesesubjects was observed for a period of two months (days 28 through 84).At any time during the course of the study, investigators couldadminister additional therapy of intravitreal injection of an anti-VEGFagent, for example, ranibizumab, bevacizumab, and/or aflibercept, ifconsidered by the investigator to be medically necessary. Retinalthickness as measured by ocular coherence tomography and best-correctedvisual acuity as measured by a standard vision test (ETDRS) wereassessed at regular intervals during the 28 day active treatment phaseand through the 2 month post-treatment observation phase, (Screening,Day 1 [baseline], Day 7, Day 14, Day 21, Day 28, Day 42, Day 56 and Day84). The main efficacy outcomes for the study were change in CRT andvisual acuity over time with treatment.

FIG. 46 depicts the results of two phase three studies to determine theeffect of intravitreal injections of ranibizumab in patients withdiabetic macular edema. In this study, patients received intravitrealinjections with either 0.3 mg (♦) or 0.5 mg (▪) ranibizumab monthly,whereas the control group (▴) received placebo. As depicted in FIG. 46the reduction in Central Foveal Thickness (CFT) for both the 0.3 mg and0.5 mg cohorts were essentially identical. As shown in FIG. 46, the twogroups receiving ranibizumab had a reduction in Central Foveal Thicknessof approximately 120 to 160 μm from day 7 to 1 month after the firstinjection of ranibizumab.

FIG. 47 depicts the results of a study wherein 4 patients received 5 mgof4-{(S)-2-[(S)-2-methoxycarbonylamino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid subcutaneously twice daily for 28 days and subsequently weretreated in one or both eyes (7 eyes total) with either ranibizumab (0.3or 0.5 mg) or aflibercept (2 mg) by intravitreal injection at thediscretion of the study investigator.

FIG. 47 is read as follows. At 14-28 days post ranibizumab oraflibercept, 1 patient eye had a Central Foveal Reduction of between50-100 μm. 1 patient eye had a Central Foveal Reduction of between150-200 μm. 1 patient eye had a Central Foveal Reduction of between200-250 μm. 1 patient eye had a Central Foveal Reduction of between300-350 μm. 2 patient eyes had a Central Foveal Reduction of between350-400 μm. 1 patient eye had a Central Foveal Reduction of between450-500 μm. The mean change in Central Foveal Thickness was −289 μm,approximately double the reduction seen after ranibizumab injection inthe study in FIG. 46.

FIG. 48 depicts the results of two phase three studies performed todetermine the effect of intravitreal injections of ranibizumab inpatients with diabetic macular edema. Results of these studies were usedto determine the effectiveness of the disclosed methods for treatingocular diseases. The control group is represented by (♦). Patientsreceiving 0.5 mg of ranibizumab monthly via ocular injection arerepresented by (▪). As shown in FIG. 48, the group receiving ranibizumabhad an increase in visual acuity of approximately 4 to 6 letters fromday 7 to 1 month after the first injection of ranibizumab.

FIG. 49 depicts the increased visual acuity of a study wherein 4patients received 5 mg of4-{(S)-2-[(S)-2-methoxycarbonylamino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid subcutaneously twice daily for 28 days, and subsequently weretreated with either ranibizumab (0.3 or 0.5 mg) or aflibercept (2 mg) byintravitreal injection at the discretion of the study investigator. FIG.49 is read as follows. At 14-28 days post ranibizumab or aflibercept, 1patient eye had an increase of from 16 to 18 letters improvement. 2patient eyes had an increase of from 14 to 16 letters improvement. 1patient eye had an increase of from 10 to 12 letters improvement. 1patient eye had an increase of from 6 to 8 letters improvement. 1patient eye had an increase of from 2 to 4 letters improvement. 1patient eye had a decrease of from 2 to 4 letters. The mean change inVisual Acuity was 9 letters, approximately 3 to 5 letters moreimprovement than seen in the benchmark study of ranibizumab alonedepicted in FIG. 48.

FIG. 50 represents the results of a single patient. The eye having thegreater Central Foveal Thickness (CFT) was chosen as the study eye. Fromday 1, the patient was given 5 mg of4-{(S)-2-[(S)-2-methoxycarbonylamino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid subcutaneously twice daily. At week 3 (21 days, indicated by arrow)the fellow eye was treated with 0.5 mg of ranibizumab by injection. Atweek 6 (42 days, indicated by arrow) the study eye was treated with 0.5mg of ranibizumab.

The CFT of the fellow eye fell significantly (350 μm) by week 4 (28days). As a result, a pronounced reduction in CFT was observed in thestudy eye from day 21 to day 28 (approximately 250 μm). By the nextmonitoring point, week 6, the effects of the systemically-receivedranibizumab were no longer present and the CFT returned to approximately775 μm. At week 6, the study eye was treated with an intravitrealinjection of 0.5 mg of ranibizumab. By week 8, an overall reduction inCFT of approximately 500 μm was observed, and the CFT of the subject eyewas approximately 225 μm. Compared to the study depicted in FIG. 46,wherein the average change in CFT at one month after ranibizumabinjection was approximately 160 mm, the combination method providedsubstantially-greater reductions at 2-4 weeks following ranibizumabinjection.

FIG. 51 represents the results of a single patient. The eye having thegreater CFT was chosen as the Study Eye. The patient from day one wasgiven 5 mg of4-{(S)-2-[(S)-2-methoxycarbonylamino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid subcutaneously twice daily. At week 4 (28 days, indicated by arrow)the fellow eye was rescued with 2 mg of aflibercept. After rescue, thefellow eye had a CFT reduction of approximately 400 μm. At week 6 (42days, indicated by arrow) the study eye was rescued with 2 mg ofaflibercept. After rescue, the study eye had a CFT reduction ofapproximately 300 μm. Unlike the results depicted for the ranibizumabprotocol, no effects of the systemically-delivered aflibercept wereobserved in the fellow eye. From onset of the study, a reduction wasobserved of CFT in the study eye and the fellow eye of approximately 300μm and 280 μm, respectively.

FIG. 52 graphically represents the results of a choroidalneovascularization murine test involving an active control, aflibercept(Eylea™),4-{(S)-2-[(S)-2-methoxycarbonylamino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid, and a combination of aflibercept and4-{(S)-2-[(S)-2-methoxycarbonylamino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid. Rupture of Burch's membrane in three locations of the eye wasinduced by laser. Control animals were given intraocular injections ofphosphate buffered saline (PBS). Animals treated with afliberceptreceived one intraocular 40 μg dose of the drug on the day of lasertreatment. The mice were then treated with either4-{(S)-2-[(S)-2-methoxycarbonylamino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl]thiazol-4-yl]ethyl}phenylsulfamicacid at 20 mg/kg by subcutaneous injection twice daily, or PBS injectiontwice daily. This protocol yielded four groups of mice: a negativecontrol group treated with intraocular and subcutaneous PBS, amonotherapy group treated with intraocular aflibercept and subcutaneousPBS; a monotherapy group treated with intraocular PBS and subcutaneousinjections of4-{(S)-2-[(S)-2-methoxycarbonylamino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl]thiazol-4-yl]ethyl}phenylsulfamicacid; and a combination therapy group receiving one intraocularinjection of 40 μg of the drug on the day of laser treatment and 20mg/kg subcutaneous injections twice daily.

FIGS. 53A-D depict the flat mounts of excised choroidal tissue stainedwith FITC-labeled Griffonia simplicifolia (GSA). The extent of choroidalneovasculature is evident in the control sample, FIG. 53A. FIG. 53Brepresents the extent of neovascularization in the choroidal tissue ofanimals treated with aflibercept. FIG. 53C represents animals treatedwith4-{(S)-2-[(S)-2-methoxycarbonylamino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid. FIG. 53D represents the extent of neovascularization present inanimals having a combined therapy of aflibercept and4-{(S)-2-[(S)-2-methoxycarbonylamino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl]thiazol-4-yl]ethyl}phenylsulfamicacid.

Example 10: Solubility of Compounds of the Disclosure

The room temperature aqueous solubility (mg/mL) of the compound(4-{(S)-2[(S)-2-methoxycarbonylamino]-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid) in water, HPβCD, Poloxamer 407, andsulfobutylether-β-cyclodextrin, is provided in TABLE III. Solubility insaline for the test compound is reduced presumably due to the common ioneffect. All the solubilizing agents tested provided good improvements inaqueous solubility of the test compound.

TABLE III Solubility % HPβCD  0 27 10 45 20 57 30 72 % SBE-β-CD 15 44 %Poloxamer 407 20 44

The solubility (mg/mL) of the test compound in mixtures of HPβCD andPEG400 is illustrated in TABLE IV. Use of either HPβCD or PEG400individually provided an increase in solubility. However, addition ofPEG400 to a mixture of the test compound and HPβCD caused an erosion ofsolubility, with solubility being inversely proportional to the amountof PEG400.

TABLE IV % HPβCD % PEG400 Solubility (mg/mL) 0 15 30 0 30 68 15 0 59 155 57 15 10 34 15 15 6

TABLE V contains aqueous solution formulations of the test compoundabove with the denoted solvents that have been prepared and shown to bechemically stable through 1 month at 50° C., and physically stable at 5°C., at ambient temperature at 50° C. The formulations are more stable atpH values above pH 4. The target pH range for the formulations is pH 7+/−0.5 pH units.

TABLE V Formulation Concentration of test compound 10% HPβCD 15 mg/mL25% HPβCD 50 mg/mL 30% HPβCD 50 mg/mL 15% HPβCD/0.25% saline 40mg/mL^(a) 4.5% mannitol 5 mg/mL^(b) ^(a)Evaluated for short-termphysical stability at 5° C. and ambient temperature. ^(b)Physically andchemically stable through one week at room temperature and one week at50° C.

Embodiments

The following are illustrative embodiments.

Embodiment 1

A compound of formula:

wherein: Aryl¹ is an aryl group which is substituted or unsubstituted;Aryl² is an aryl group which is substituted or unsubstituted; X isalkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, anamide linkage, an ester linkage, a thioether linkage, a carbamatelinkage, a carbonate linkage, a ureido linkage, a sulfone linkage, anyof which is substituted or unsubstituted, or a chemical bond; and Y isH, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g),any of which is substituted or unsubstituted, or

wherein: L is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L is bound forms an amide linkage, a carbamate linkage, a ureidolinkage, or a sulfonamide linkage, or a chemical bond, or together withany of R^(a), R^(b), R^(c), and R^(d) forms a ring that is substitutedor unsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L, R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a pharmaceutically-acceptable salt, tautomer, orzwitterion thereof.

Embodiment 2

The compound of embodiment 1, wherein: Aryl¹ is substituted orunsubstituted phenyl; Aryl² is substituted or unsubstituted heteroaryl;and X is alkylene.

Embodiment 3

The compound of any one of embodiments 1 and 2, wherein: Aryl¹ issubstituted phenyl; Aryl² is substituted heteroaryl; and X is methylene.

Embodiment 4

The compound of any one of embodiments 1-3, wherein the compound is ofthe formula:

wherein Aryl¹ is para-substituted phenyl; Aryl² is substitutedheteroaryl; X is methylene; L is alkylene, alkenylene, or alkynylene,any of which is substituted or unsubstituted, or together with thenitrogen atom to which L is bound forms an amide linkage, a carbamatelinkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond;R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(b) is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, any of which is substituted or unsubstituted; R^(c) isH or alkyl which is substituted or unsubstituted; and R^(d) is H oralkyl which is substituted or unsubstituted.

Embodiment 5

The compound of any one of embodiments 1-4, wherein the compound is ofthe formula:

Embodiment 6

The compound of any one of embodiments 1-4, wherein the compound is ofthe formula:

Embodiment 7

The compound of embodiment 4, wherein: Aryl¹ is para-substituted phenyl;Aryl² is a substituted thiazole moiety; X is methylene; L together withthe nitrogen atom to which L is bound forms a carbamate linkage; R^(a)is alkyl, which is substituted or unsubstituted; R^(b) is arylalkyl,which is substituted or unsubstituted; R^(e) is H; and R^(d) is H.

Embodiment 8

The compound of any one of embodiments 1-7, wherein Aryl² is:

wherein:R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxygroup, an ether group, a carboxylic acid group, a carboxaldehyde group,an ester group, an amine group, an amide group, a carbonate group, acarbamate group, a ureido group, a thioether group, a thioester group, athioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted; and R^(f) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl,alkynyl, an alkoxy group, an ether group, a carboxylic acid group, acarboxaldehyde group, an ester group, an amine group, an amide group, acarbonate group, a carbamate group, a ureido group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted.

Embodiment 9

The compound of embodiment 8, wherein: R^(e) is H, OH, F, Cl, Br, I,alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; and R^(f) is H, OH, F, Cl, Br, I, alkyl,an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted.

Embodiment 10

The compound of any one of embodiments 8-9, wherein: R^(e) is H, OH, F,Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted orunsubstituted; and R^(f) is alkyl, aryl, heterocyclyl, or heteroaryl,any of which is substituted or unsubstituted.

Embodiment 11

The compound of any one of embodiments 8-10, wherein: Aryl¹ is4-phenylsulfamic acid; R^(a) is alkyl, which is substituted orunsubstituted; R^(b) is arylalkyl, which is substituted orunsubstituted; R^(e) is H; and R^(f) is heteroaryl.

Embodiment 12

The compound of any one of embodiments 1-5, and 7-11, wherein thecompound is:

Embodiment 13

The compound of any one of embodiments 1-4, and 6-11, wherein thecompound is:

Embodiment 14

A compound of formula:

wherein:Aryl¹ is an aryl group which is substituted or unsubstituted; Aryl² isan aryl group which is substituted or unsubstituted; X is alkylene,alkenylene, alkynylene, an ether linkage, an amine linkage, an amidelinkage, an ester linkage, a thioether linkage, a carbamate linkage, acarbonate linkage, a ureido linkage, a sulfone linkage, any of which issubstituted or unsubstituted, or a chemical bond; L is alkylene,alkenylene, or alkynylene, any of which is substituted or unsubstituted,or together with the nitrogen atom to which L is bound forms an amidelinkage, a carbamate linkage, a ureido linkage, or a sulfonamidelinkage, or a chemical bond, or together with any of R^(a), R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(b), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(b) is H,alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(e) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a pharmaceutically-acceptable salt, tautomer, orzwitterion thereof.

Embodiment 15

The compound of embodiment 14, wherein: Aryl¹ is substituted orunsubstituted phenyl; Aryl² is substituted or unsubstituted heteroaryl;and X is alkylene.

Embodiment 16

The compound of any one of embodiments 14-15, wherein: Aryl¹ issubstituted phenyl; Aryl² is substituted heteroaryl; and X is methylene.

Embodiment 17

The compound of any one of embodiments 14-16, wherein: Aryl¹ ispara-substituted phenyl; Aryl² is substituted heteroaryl; X ismethylene; L is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L is bound forms an amide linkage, a carbamate linkage, a ureidolinkage, or a sulfonamide linkage, or a chemical bond; R^(a) is H,alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(b) is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, any of which is substituted or unsubstituted; R^(e) isH or alkyl which is substituted or unsubstituted; and R^(d) is H oralkyl which is substituted or unsubstituted.

Embodiment 18

The compound of any one of embodiments 14-17, wherein: Aryl¹ ispara-substituted phenyl; Aryl² is a substituted thiazole moiety; X ismethylene; L together with the nitrogen atom to which L is bound forms acarbamate linkage; R^(a) is alkyl, which is substituted orunsubstituted; R^(b) is arylalkyl, which is substituted orunsubstituted; R^(e) is H; and R^(d) is H.

Embodiment 19

The compound of any one of embodiments 14-18, wherein Aryl² is:

wherein:R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxygroup, an ether group, a carboxylic acid group, a carboxaldehyde group,an ester group, an amine group, an amide group, a carbonate group, acarbamate group, a ureido group, a thioether group, a thioester group, athioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted; and R^(f) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl,alkynyl, an alkoxy group, an ether group, a carboxylic acid group, acarboxaldehyde group, an ester group, an amine group, an amide group, acarbonate group, a carbamate group, a ureido group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted.

Embodiment 20

The compound of embodiment 19, wherein: R^(e) is H, OH, F, Cl, Br, I,alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; and R^(f) is H, OH, F, Cl, Br, I, alkyl,an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted.

Embodiment 21

The compound of any one of embodiments 19-20, wherein: R^(e) is H, OH,F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted orunsubstituted; and R^(f) is alkyl, aryl, heterocyclyl, or heteroaryl,any of which is substituted or unsubstituted.

Embodiment 22

The compound of any one of embodiments 19-21, wherein: Aryl¹ is4-phenylsulfamic acid; R^(a) is alkyl, which is substituted orunsubstituted; R^(b) is arylalkyl, which is substituted orunsubstituted; R^(e) is H; and R^(f) is heteroaryl.

Embodiment 23

The compound of any one of embodiments 14-21, wherein the compound is:

Embodiment 24

A pharmaceutical composition comprising two Tie-2 activators, whereinthe two Tie-2 activators are stereoisomers of one another, wherein thepharmaceutical composition is in a unit dosage form.

Embodiment 25

The pharmaceutical composition of embodiment 24, wherein thestereoisomers are enantiomers of one another.

Embodiment 26

The pharmaceutical composition of embodiment 24, wherein thestereoisomers are diastereomers of one another.

Embodiment 27

The pharmaceutical composition of any one of embodiments 24-26, whereinthe two Tie-2 activators bind HPTP-beta.

Embodiment 28

The pharmaceutical composition of any one of embodiments 24-27, whereinthe two Tie-2 activators inhibit HPTP-beta.

Embodiment 29

The pharmaceutical composition of any one of embodiments 24-28, whereinone of the Tie-2 activators is present in an amount that is no greaterthan 1% of the amount of the other Tie-2 activator.

Embodiment 30

The pharmaceutical composition of any one of embodiments 24-29, whereinthe two Tie-2 activators are small organic molecules.

Embodiment 31

A pharmaceutical composition comprising a Tie-2 activator and astereoisomer of the Tie-2 activator, wherein the stereoisomer activatesTie-2 with a potency that is from about 0.001% to about 100% the potencyof the Tie-2 activator.

Embodiment 32

The pharmaceutical composition of embodiment 31, wherein thestereoisomer of the Tie-2 activator is an enantiomer of the Tie-2activator.

Embodiment 33

The pharmaceutical composition of embodiment 31, wherein thestereoisomer of the Tie-2 activator is a diastereomer of the Tie-2activator.

Embodiment 34

The pharmaceutical composition of any one of embodiments 31-33, whereinthe stereoisomer activates Tie-2 with a potency that is from about 0.01%to about 10% the potency of the Tie-2 activator.

Embodiment 35

The pharmaceutical composition of any one of embodiments 31-34, whereinthe stereoisomer activates Tie-2 with a potency that is from about 0.01%to about 1% the potency of the Tie-2 activator.

Embodiment 36

The pharmaceutical composition of any one of embodiments 31-35, whereinthe stereoisomer activates Tie-2 with a potency that is from about 0.01%to about 0.5% the potency of the Tie-2 activator.

Embodiment 37

The pharmaceutical composition of any one of embodiments 31-36, whereinthe stereoisomer binds HPTP-beta.

Embodiment 38

The pharmaceutical composition of any one of embodiments 31-37, whereinthe stereoisomer inhibits HPTP-beta.

Embodiment 39

The pharmaceutical composition of any one of embodiments 31-38, whereinthe stereoisomer is a small organic molecule.

Embodiment 40

A method comprising contacting with a reaction mixture a compound offormula:

wherein:Aryl¹ is an aryl group which is substituted or unsubstituted; Aryl² isan aryl group which is substituted or unsubstituted; X is alkylene,alkenylene, alkynylene, an ether linkage, an amine linkage, an amidelinkage, an ester linkage, a thioether linkage, a carbamate linkage, acarbonate linkage, a ureido linkage, a sulfone linkage, any of which issubstituted or unsubstituted, or a chemical bond; L is alkylene,alkenylene, or alkynylene, any of which is substituted or unsubstituted,or together with the nitrogen atom to which L is bound forms an amidelinkage, a carbamate linkage, a ureido linkage, or a sulfonamidelinkage, or a chemical bond, or together with any of R^(a), R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(b), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(b) is H,alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a salt, tautomer, or zwitterion thereof, wherein astereocenter of the compound or salt thereof inverts, thereby providinga stereoisomer of the compound or a salt, tautomer, or zwitterion of thestereoisomer.

Embodiment 41

The method of embodiment 40, wherein the reaction mixture comprises abase.

Embodiment 42

The method of any one of embodiments 40-41, wherein the compound is:

Embodiment 43

The method of any one of embodiments 40-42, wherein the stereoisomer is:

Embodiment 44

A method comprising mixing with a reaction mixture a compound offormula:

or a salt thereof, and a starting material to provide a product offormula:

or a salt, tautomer, or zwitterion thereof, wherein: Aryl¹ is an arylgroup which is substituted or unsubstituted; Aryl² is an aryl groupwhich is substituted or unsubstituted; X is alkylene, alkenylene,alkynylene, an ether linkage, an amine linkage, an amide linkage, anester linkage, a thioether linkage, a carbamate linkage, a carbonatelinkage, a ureido linkage, a sulfone linkage, any of which issubstituted or unsubstituted, or a chemical bond; L is alkylene,alkenylene, or alkynylene, any of which is substituted or unsubstituted,or together with the nitrogen atom to which L is bound forms an amidelinkage, a carbamate linkage, a ureido linkage, or a sulfonamidelinkage, or a chemical bond, or together with any of R^(a), R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(b), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(b) is H,alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted.

Embodiment 45

The method of embodiment 44, wherein the compound is:

or a salt thereof.

Embodiment 46

The method of any one of embodiments 44-45, wherein the startingmaterial is:

or a salt, tautomer, or zwitterion thereof.

Embodiment 47

The method of any one of embodiments 44-46, wherein the startingmaterial is:

or a salt thereof, wherein N group is a functional group that contains anitrogen atom.

Embodiment 48

the method of any one of embodiments 44-47, wherein the startingmaterial is:

or a salt thereof.

Embodiment 49

The method of any one of embodiments 44-48, wherein the product is:

or a salt thereof.

What is claimed is:
 1. A compound of formula:

wherein: Aryl¹ is a phenylsulfamic acid group; Aryl² is

wherein: R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, an amine group, an amide group, acarbonate group, a carbamate group, a ureido group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(f) is H, OH, F, Cl, Br, I, CN, alkyl,alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acidgroup, a carboxaldehyde group, an ester group, an amine group, an amidegroup, a carbonate group, a carbamate group, a ureido group, a thioethergroup, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted; X is alkylene, alkenylene,alkynylene, an ether linkage, an amine linkage, an amide linkage, anester linkage, a thioether linkage, a carbamate linkage, a carbonatelinkage, a ureido linkage, or a sulfone linkage, any of which issubstituted or unsubstituted; and Y is aryl, heteroaryl, NH(aryl),NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g), any of which is substituted orunsubstituted, or

 wherein: L is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L is bound forms an amide linkage, a carbamate linkage, a ureidolinkage, or a sulfonamide linkage, or a chemical bond, or together withany of R^(a), R^(b), R^(c), and R^(d) forms a ring that is substitutedor unsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L, R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a pharmaceutically-acceptable salt, tautomer, orzwitterion thereof.
 2. The compound of claim 1, wherein: X is alkylene.3. The compound of claim 2, wherein: X is methylene.
 4. The compound ofclaim 3, wherein the compound is of the formula:

wherein X is methylene; L is alkylene, alkenylene, or alkynylene, any ofwhich is substituted or unsubstituted, or together with the nitrogenatom to which L is bound forms an amide linkage, a carbamate linkage, aureido linkage, or a sulfonamide linkage, or a chemical bond; R^(a) isH, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(b) is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, any of which is substituted or unsubstituted; R^(c) isH or alkyl which is substituted or unsubstituted; and R^(d) is H oralkyl which is substituted or unsubstituted.
 5. The compound of claim 4,wherein the compound is of the formula:


6. The compound of claim 4, wherein the compound is of the formula:


7. The compound of claim 4, wherein: X is methylene; L together with thenitrogen atom to which L is bound forms a carbamate linkage; R^(a) isalkyl, which is substituted or unsubstituted; R^(b) is arylalkyl, whichis substituted or unsubstituted; R^(c) is H; and R^(d) is H.
 8. Thecompound of claim 7, wherein Aryl² is:


9. The compound of claim 8, wherein: R^(e) is H, OH, F, Cl, Br, I,alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; and R^(f) is H, OH, F, Cl, Br, I, alkyl,an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted.
 10. The compound of claim 8, wherein: R^(e) is H, OH, F,Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted orunsubstituted; and R^(f) is alkyl, aryl, heterocyclyl, or heteroaryl,any of which is substituted or unsubstituted.
 11. The compound of claim8, wherein: Aryl¹ is 4-phenylsulfamic acid; R^(a) is alkyl, which issubstituted or unsubstituted; R^(b) is arylalkyl, which is substitutedor unsubstituted; R^(e) is H; and R^(f) is heteroaryl.
 12. The compoundof claim 1, wherein the compound is:


13. The compound of claim 1, wherein the compound is:


14. A pharmaceutical composition comprising two Tie-2 activators,wherein the two Tie-2 activators are stereoisomers of one another,wherein one of the Tie-2 activators is a compound of the formula:

wherein: Aryl¹ is a phenylsulfamic acid group; Aryl² is

wherein: R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, an amine group, an amide group, acarbonate group, a carbamate group, a ureido group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(f) is H, OH, F, Cl, Br, I, CN, alkyl,alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acidgroup, a carboxaldehyde group, an ester group, an amine group, an amidegroup, a carbonate group, a carbamate group, a ureido group, a thioethergroup, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted; X is alkylene, alkenylene,alkynylene, an ether linkage, an amine linkage, an amide linkage, anester linkage, a thioether linkage, a carbamate linkage, a carbonatelinkage, a ureido linkage, or a sulfone linkage, any of which issubstituted or unsubstituted; and Y is aryl, heteroaryl, NH(aryl),NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g), any of which is substituted orunsubstituted, or

 wherein: L is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L is bound forms an amide linkage, a carbamate linkage, a ureidolinkage, or a sulfonamide linkage, or a chemical bond, or together withany of R^(a), R^(b), R^(c), and R^(d) forms a ring that is substitutedor unsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L, R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a pharmaceutically-acceptable salt, tautomer, orzwitterion thereof; and wherein the pharmaceutical composition is in aunit dosage form.
 15. The pharmaceutical composition of claim 14,wherein the stereoisomers are enantiomers of one another.
 16. Thepharmaceutical composition of claim 14, wherein the stereoisomers arediastereomers of one another.
 17. The pharmaceutical composition ofclaim 14, wherein the two Tie-2 activators bind HPTP-beta.
 18. Thepharmaceutical composition of claim 14, wherein the two Tie-2 activatorsinhibit HPTP-beta.
 19. The pharmaceutical composition of claim 14,wherein one of the Tie-2 activators is present in an amount that is nogreater than 1% of the amount of the other Tie-2 activator.
 20. Thepharmaceutical composition of claim 14, wherein one of the Tie-2activators is a compound of the formula:

or a pharmaceutically-acceptable salt or zwitterion thereof.
 21. Thepharmaceutical composition of claim 14, wherein the other of the Tie-2activators is a compound of the formula:

or a pharmaceutically-acceptable salt or zwitterion thereof.
 22. Apharmaceutical composition comprising a Tie-2 activator and astereoisomer of the Tie-2 activator, wherein the stereoisomer of theTie-2 activator is a compound of the formula:

wherein: Aryl¹ is a phenylsulfamic acid group; Aryl² is

wherein: R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, an amine group, an amide group, acarbonate group, a carbamate group, a ureido group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(f) is H, OH, F, Cl, Br, I, CN, alkyl,alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acidgroup, a carboxaldehyde group, an ester group, an amine group, an amidegroup, a carbonate group, a carbamate group, a ureido group, a thioethergroup, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted; X is alkylene, alkenylene,alkynylene, an ether linkage, an amine linkage, an amide linkage, anester linkage, a thioether linkage, a carbamate linkage, a carbonatelinkage, a ureido linkage, or a sulfone linkage, any of which issubstituted or unsubstituted; and Y is aryl, heteroaryl, NH(aryl),NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g), any of which is substituted orunsubstituted, or

 wherein: L is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L is bound forms an amide linkage, a carbamate linkage, a ureidolinkage, or a sulfonamide linkage, or a chemical bond, or together withany of R^(a), R^(b), R^(c), and R^(d) forms a ring that is substitutedor unsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L, R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a pharmaceutically-acceptable salt, tautomer, orzwitterion thereof; and wherein the stereoisomer activates Tie-2 with apotency that is from about 0.001% to about 100% the potency of the Tie-2activator.
 23. The pharmaceutical composition of claim 22, wherein thestereoisomer of the Tie-2 activator is an enantiomer of the Tie-2activator.
 24. The pharmaceutical composition of claim 22, wherein thestereoisomer of the Tie-2 activator is a diastereomer of the Tie-2activator.
 25. The pharmaceutical composition of claim 22, wherein thestereoisomer activates Tie-2 with a potency that is from about 0.01% toabout 10% the potency of the Tie-2 activator.
 26. The pharmaceuticalcomposition of claim 22, wherein the stereoisomer activates Tie-2 with apotency that is from about 0.01% to about 1% the potency of the Tie-2activator.
 27. The pharmaceutical composition of claim 22, wherein thestereoisomer activates Tie-2 with a potency that is from about 0.01% toabout 0.5% the potency of the Tie-2 activator.
 28. The pharmaceuticalcomposition of claim 22, wherein the stereoisomer binds HPTP-beta. 29.The pharmaceutical composition of claim 22, wherein the stereoisomerinhibits HPTP-beta.
 30. The pharmaceutical composition of claim 22,wherein the Tie-2 activator is a compound of the formula:

wherein: Aryl¹ is a phenylsulfamic acid group; Aryl² is

wherein: R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, an amine group, an amide group, acarbonate group, a carbamate group, a ureido group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(f) is H, OH, F, Cl, Br, I, CN, alkyl,alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acidgroup, a carboxaldehyde group, an ester group, an amine group, an amidegroup, a carbonate group, a carbamate group, a ureido group, a thioethergroup, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted; X is alkylene, alkenylene,alkynylene, an ether linkage, an amine linkage, an amide linkage, anester linkage, a thioether linkage, a carbamate linkage, a carbonatelinkage, a ureido linkage, or a sulfone linkage, any of which issubstituted or unsubstituted; and Y is aryl, heteroaryl, NH(aryl),NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g), any of which is substituted orunsubstituted, or

 wherein: L is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L is bound forms an amide linkage, a carbamate linkage, a ureidolinkage, or a sulfonamide linkage, or a chemical bond, or together withany of R^(a), R^(b), R^(c), and R^(d) forms a ring that is substitutedor unsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L, R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a pharmaceutically-acceptable salt or zwitterionthereof.
 31. The pharmaceutical composition of claim 22, wherein thestereoisomer of the Tie-2 activator is a compound of the formula:

or a pharmaceutically-acceptable salt or zwitterion thereof.
 32. Thepharmaceutical composition of claim 22, wherein the Tie-2 activator is acompound of the formula:

or a pharmaceutically-acceptable salt or zwitterion thereof.
 33. Amethod comprising contacting with a reagent a compound of formula:

wherein: Aryl¹ is a phenylsulfamic acid group; Aryl² is

wherein: R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, an amine group, an amide group, acarbonate group, a carbamate group, a ureido group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(f) is H, OH, F, Cl, Br, I, CN, alkyl,alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acidgroup, a carboxaldehyde group, an ester group, an amine group, an amidegroup, a carbonate group, a carbamate group, a ureido group, a thioethergroup, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted; X is alkylene, alkenylene,alkynylene, an ether linkage, an amine linkage, an amide linkage, anester linkage, a thioether linkage, a carbamate linkage, a carbonatelinkage, a ureido linkage, or a sulfone linkage, any of which issubstituted or unsubstituted; L is alkylene, alkenylene, or alkynylene,any of which is substituted or unsubstituted, or together with thenitrogen atom to which L is bound forms an amide linkage, a carbamatelinkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond,or together with any of R^(a), R^(b), R^(c), and R^(d) forms a ring thatis substituted or unsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl,aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, any of which is substituted or unsubstituted, ortogether with any of L, R^(b), R^(e), and R^(d) forms a ring that issubstituted or unsubstituted; R^(b) is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, any of which is substituted or unsubstituted, ortogether with any of L, R^(a), R^(c), and R^(d) forms a ring that issubstituted or unsubstituted; R^(c) is H or alkyl which is substitutedor unsubstituted, or together with any of L, R^(a), R^(b), and R^(d)forms a ring that is substituted or unsubstituted; R^(d) is H or alkylwhich is substituted or unsubstituted, or together with any of L, R^(a),R^(b), and R^(e) forms a ring that is substituted or unsubstituted; andR^(g) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or a salt, tautomer, or zwitterionthereof, wherein a stereocenter of the compound or salt thereof inverts,thereby providing a stereoisomer of the compound or a salt, tautomer, orzwitterion of the stereoisomer, wherein the stereoisomer is a compoundof the formula:

 wherein: Aryl¹ is a substituted carbocyclic aryl group phenylsulfamicacid group; Aryl² is

wherein: R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, an amine group, an amide group, acarbonate group, a carbamate group, a ureido group, a thioether group, athioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(f) is H, OH, F, Cl, Br, I, CN, alkyl,alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acidgroup, a carboxaldehyde group, an ester group, an amine group, an amidegroup, a carbonate group, a carbamate group, a ureido group, a thioethergroup, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted; X is alkylene, alkenylene,alkynylene, an ether linkage, an amine linkage, an amide linkage, anester linkage, a thioether linkage, a carbamate linkage, a carbonatelinkage, a ureido linkage, or a sulfone linkage, any of which issubstituted or unsubstituted; and Y is aryl, heteroaryl, NH(aryl),NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g), any of which is substituted orunsubstituted, or

 wherein: L is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L is bound forms an amide linkage, a carbamate linkage, a ureidolinkage, or a sulfonamide linkage, or a chemical bond, or together withany of R^(a), R^(b), R^(c), and R^(d) forms a ring that is substitutedor unsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L, R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a pharmaceutically-acceptable salt, tautomer, orzwitterion thereof.
 34. The method of claim 33, wherein the reagent is abase.
 35. The method of claim 33, wherein the compound is:


36. The method of claim 35, wherein the stereoisomer is: